Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors

ABSTRACT

This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.

FIELD OF THE INVENTION

[0001] This invention relates to the use of a group of aryl ureas intreating raf mediated diseases, and pharmaceutical compositions for usein such therapy.

BACKGROUND OF THE INVENTION

[0002] The p21^(ras) oncogene is a major contributor to the developmentand progression of human solid cancers and is mutated in 30% of allhuman cancers (Bolton et al. Ann. Rep. Med. Chem. 1994, 29, 165-74; Bos.Cancer Res. 1989, 49, 4682-9). In its normal, unmutated form, the rasprotein is a key element of the signal transduction cascade directed bygrowth factor receptors in almost all tissues (Avruch et al. TrendsBiochem. Sci. 1994, 19, 279-83). Biochemically, ras is a guaninenucleotide binding protein, and cycling between a GTP-bound activatedand a GDP-bound resting form is strictly controlled by ras' endogenousGTPase activity and other regulatory proteins. In the ras mutants incancer cells, the endogenous GTPase activity is alleviated and,therefore, the protein delivers constitutive growth signals todownstream effectors such as the enzyme raf kinase. This leads to thecancerous growth of the cells which carry these mutants (Magnuson et al.Semin. Cancer Biol. 1994, 5, 247-53). It has been shown that inhibitingthe effect of active ras by inhibiting the raf kinase signaling pathwayby administration of deactivating antibodies to raf kinase or byco-expression of dominant negative raf kinase or dominant negative MEK,the substrate of raf kinase, leads to the reversion of transformed cellsto the normal growth phenotype (see: Daum et al. Trends Biochem. Sci.1994, 19, 474-80; Fridman et al. J. Biol. Chem. 1994, 269, 30105-8.Kolch et al. (Nature 1991, 349, 426-28) have further indicated thatinhibition of raf expression by antisense RNA blocks cell proliferationin membrane-associated oncogenes. Similarly, inhibition of raf kinase(by antisense oligodeoxynucleotides) has been correlated in vitro and invivo with inhibition of the growth of a variety of human tumor types(Monia et al., Nat. Med. 1996, 2, 668-75).

SUMMARY OF THE INVENTION

[0003] The present invention provides compounds which are inhibitors ofthe enzyme raf kinase. Since the enzyme is a downstream effector ofp21^(ras), the inhibitors are useful in pharmaceutical compositions forhuman or veterinary use where inhibition of the raf kinase pathway isindicated, e.g., in the treatment of tumors and/or cancerous cell growthmediated by raf kinase. In particular, the compounds are useful in thetreatment of human or animal solid cancers, e.g., murine cancer, sincethe progression of these cancers is dependent upon the ras proteinsignal transduction cascade and therefore susceptible to treatment byinterruption of the cascade, i.e., by inhibiting raf kinase.Accordingly, the compounds of the invention are useful in treatingcancers, including solid cancers, such as, for example, carcinomas(e.g., of the lungs, pancreas, thyroid, bladder or colon), myeloiddisorders (e.g., myeloid leukemia) or adenomas (e.g., villous colonadenoma).

[0004] The present invention therefore provides compounds generallydescribed as aryl ureas, including both aryl and heteroaryl analogues,which inhibit the raf kinase pathway. The invention also provides amethod for treating a raf mediated disease state in humans or mammals.Thus, the invention is directed to compounds which inhibit the enzymeraf kinase and also compounds, compositions and methods for thetreatment of cancerous cell growth mediated by raf kinase wherein acompound of Formula I is administered or pharmaceutically acceptablesalt thereof.

A—D—B  (I)

[0005] In formula I, D is —NH—C(O)—NH—,

[0006] A is a substituted moiety of up to 40 carbon atoms of theformula: —L—(M—L¹)_(q), where L is a 5 or 6 membered cyclic structurebound directly to D, L¹ comprises a substituted cyclic moiety having atleast 5 members, M is a bridging group having at least one atom, q is aninteger of from 1-3; and each cyclic structure of L and L¹ contains 0-4members of the group consisting of nitrogen, oxygen and sulfur, and

[0007] B is a substituted or unsubstituted, up to tricyclic aryl orheteroaryl moiety of up to 30 carbon atoms with at least one 6-membercyclic structure bound directly to D containing 0-4 members of the groupconsisting of nitrogen, oxygen and sulfur,

[0008] wherein L¹ is substituted by at least one substituent selectedfrom the group consisting of —SO₂R_(x), —C(O)R_(x) and —C(NR_(y))R_(z),

[0009] R_(y) is hydrogen or a carbon based moiety of up to 24 carbonatoms optionally containing heteroatoms selected from N, S and O andoptionally halosubstituted, up to per halo,

[0010] R_(z) is hydrogen or a carbon based moiety of up to 30 carbonatoms optionally containing heteroatoms selected from N, S and O andoptionally substituted by halogen, hydroxy and carbon based substituentsof up to 24 carbon atoms, which optionally contain heteroatoms selectedfrom N, S and O and are optionally substituted by halogen;

[0011] R_(x) is R_(z) or NR_(a)R_(b) where R_(a) and R_(b) are

[0012] a) independently hydrogen,

[0013] a carbon based moiety of up to 30 carbon atoms optionallycontaining heteroatoms selected from N, S and O and optionallysubstituted by halogen, hydroxy and carbon based substituents of up to24 carbon atoms, which optionally contain heteroatoms selected from N, Sand O and are optionally substituted by halogen, or

[0014] —OSi(R_(f))₃ where R_(f) is hydrogen or a carbon based moiety ofup to 24 carbon atoms optionally containing heteroatoms selected from N,S and O and optionally substituted by halogen, hydroxy and carbon basedsubstituents of up to 24 carbon atoms, which optionally containheteroatoms selected from N, S and O and are optionally substituted byhalogen; or

[0015] b) R_(a) and R_(b) together form a 5-7 member heterocyclicstructure of 1-3 heteroatoms selected from N, S and O, or a substituted5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, Sand O substituted by halogen, hydroxy or carbon based substituents of upto 24 carbon atoms, which optionally contain heteroatoms selected fromN, S and O and are optionally substituted by halogen; or

[0016] c) one of R_(a) or R_(b) is —C(O)—, a C₁-C₅ divalent alkylenegroup or a substituted C₁-C₅ divalent alkylene group bound to the moietyL to form a cyclic structure with at least 5 members, wherein thesubstituents of the substituted C₁-C₅ divalent alkylene group areselected from the group consisting of halogen, hydroxy, and carbon basedsubstituents of up to 24 carbon atoms, which optionally containheteroatoms selected from N, S and O and are optionally substituted byhalogen;

[0017] where B is substituted, L is substituted or L¹ is additionallysubstituted, the substituents are selected from the group consisting ofhalogen, up to per-halo, and Wn, where n is 0-3;

[0018] wherein each W is independently selected from the groupconsisting of —CN, —CO₂R⁷, —C(O)NR⁷R⁷, —C(O)—R⁷, —NO₂, —OR⁷, —SR⁷,—NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, —Q—Ar, and carbon based moieties of upto 24 carbon atoms, optionally containing heteroatoms selected from N, Sand O and optionally substituted by one or more substituentsindependently selected from the group consisting of —CN, —CO₂R⁷,—C(O)R⁷, —C(O)NR⁷R⁷, —OR⁷, —SR⁷, —NR⁷R, —NO₂, —NR⁷C(O)R⁷, —NR⁷C(O)OR⁷and halogen up to per-halo; with each R⁷ independently selected from Hor a carbon based moiety of up to 24 carbon atoms, optionally containingheteroatoms selected from N, S and O and optionally substituted byhalogen,

[0019] wherein Q is —O—, —S—, —N(R⁷)—, —(CH₂)_(m)—, —C(O)—, —CH(OH)—,—(CH₂)_(m)O—, —(CH₂)_(m)S—, —(CH₂)_(m)N(R⁷)—, —O(CH₂)_(m)—CHX^(a)—,—CX^(a) ₂—, —S—(CH₂)_(m)— and —N(R⁷)(CH₂)_(m)—, where m=1-3, and X^(a)is halogen; and

[0020] Ar is a 5- or 6-member aromatic structure containing 0-2 membersselected from the group consisting of nitrogen, oxygen and sulfur, whichis optionally substituted by halogen, up to per-halo, and optionallysubstituted by Z_(n1), wherein n1 is 0 to 3 and each Z is independentlyselected from the group consisting of —CN, —CO₂R⁷, —C(O)R⁷, —C(O)NR⁷R⁷,—NO₂, 13 OR⁷, —SR⁷—NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, and a carbon basedmoiety of up to 24 carbon atoms, optionally containing heteroatomsselected from N, S and O and optionally substituted by one or moresubstituents selected from the group consisting of —CN, —CO₂R⁷, —COR⁷,—C(O)NR⁷R⁷, —OR⁷, —SR⁷, —NO₂, —NR⁷R⁷, —NR⁷C(O)R⁷, and —NR⁷C(O)OR⁷, withR⁷ as defined above.

[0021] In formula I, suitable hetaryl groups include, but are notlimited to, 5-12 carbon-atom aromatic rings or ring systems containing1-3 rings, at least one of which is aromatic, in which one or more,e.g., 1-4 carbon atoms in one or more of the rings can be replaced byoxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms. Forexample, B can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-,2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl,2-, 4- or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 2-, 4- or 5-thiazolyl,3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or6-pyrimidinyl, 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or-5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl,1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,1,3,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-,5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl,pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5- 6- or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 2-, 4-, 5-,6- or 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl,1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl,1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- of 9-acridinyl, or 2-, 4-, 5-, 6-, 7- or8-quinazolinyl, or additionally optionally substituted phenyl, 2- or3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or5-thiazolyl, etc. For example, B can be 4-methyl-phenyl,5-methyl-2-thienyl, 4-methyl-2-thienyl, 1-methyl-3-pyrryl,1-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or5-methyl-1,2,4-thiadiazol-2-yl.

[0022] Suitable alkyl groups and alkyl portions of groups, e.g., alkoxy,etc. throughout include methyl, ethyl, propyl, butyl, etc., includingall straight-chain and branched isomers such as isopropyl, isobutyl,sec-butyl, tert-butyl, etc.

[0023] Suitable aryl groups which do not contain heteroatoms include,for example, phenyl and 1- and 2-naphthyl.

[0024] The term “cycloalkyl”, as used herein, refers to cyclicstructures with or without alkyl substituents such that, for example,“C₄ cycloalkyl” includes methyl substituted cyclopropyl groups as wellas cyclobutyl groups. The term “cycloalkyl”, as used herein alsoincludes saturated heterocyclic groups.

[0025] Suitable halogen groups include F, Cl, Br, and/or I, from one toper-substitution (i.e. all H atoms on a group replaced by a halogenatom) being possible where an alkyl group is substituted by halogen,mixed substitution of halogen atom types also being possible on a givenmoiety.

[0026] The invention also relates to compounds per se, of formula I.

[0027] The present invention is also directed to pharmaceuticallyacceptable salts of formula I. Suitable pharmaceutically acceptablesalts are well known to those skilled in the art and include basic saltsof inorganic and organic acids, such as hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, methanesulphonic acid,trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, aceticacid, trifluoroacetic acid, malic acid, tartaric acid, citric acid,lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid,benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. Inaddition, pharmaceutically acceptable salts include acid salts ofinorganic bases, such as salts containing alkaline cations (e.g., Li⁺Na⁺ or K⁺), alkaline earth cations (e.g., Mg⁺², Ca⁺² or Ba⁺²), theammonium cation, as well as acid salts of organic bases, includingaliphatic and aromatic substituted ammonium, and quaternary ammoniumcations, such as those arising from protonation or peralkylation oftriethylamine, N,N-diethylamine, N,N-dicyclohexylamine, lysine,pyridine, N,N-dimethylaminopyridine (DMAP), 1,4-diazabiclo[2.2.2]octane(DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0028] A number of the compounds of Formula I possess asymmetric carbonsand can therefor exist in racemic and optically active forms. Methods ofseparation of enantiomeric and diastereomeric mixtures are well known toone skilled in the art. The present invention encompasses any isolatedracemic or optically active form of compounds described in Formula Iwhich possess raf inhibitory activity.

GENERAL PREPARATIVE METHODS

[0029] The compounds of Formula I may be prepared by the use of knownchemical reactions and procedures, some from starting materials whichare commercially available. Nevertheless, general preparative methodsare provided below to aid one skilled in the art in synthesizing thesecompounds, with more detailed examples being provided in theExperimental section which follows.

[0030] Substituted anilines may be generated using standard methods(March. Advanced Organic Chemistry, 3^(rd) Ed.; John Wiley: New York(1985). Larock. Comprehensive Organic Transformations; VCH Publishers:New York (1989)). As shown in Scheme I, aryl amines are commonlysynthesized by reduction of nitroaryls using a metal catalyst, such asNi, Pd, or Pt, and H₂ or a hydride transfer agent, such as formate,cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods;Academic Press: London, UK (1985)). Nitroaryls may also be directlyreduced using a strong hydride source, such as LiAlH₄ (Seyden-Penne.Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCHPublishers: New York (1991)), or using a zero valent metal, such as Fe,Sn or Ca, often in acidic media. Many methods exist for the synthesis ofnitroaryls (March. Advanced Organic Chemistry, 3^(rd) Ed.; John Wiley:New York (1985). Larock. Comprehensive Organic Transformations; VCHPublishers: New York (1989)).

[0031] Scheme I Reduction of Nitroaryls to Aryl Amines

[0032] Nitroaryls are commonly formed by electrophilic aromaticnitration using HNO₃, or an alternative NO₂ ⁺ source. Nitroaryls may befurther elaborated prior to reduction. Thus, nitroaryls substituted with

[0033] potential leaving groups (e.g. F, Cl, Br, etc.) may undergosubstitution reactions on treatment with nucleophiles, such as thiolate(exemplified in Scheme II) or phenoxide. Nitroaryls may also undergoUllman-type coupling reactions (Scheme II).

[0034] Scheme II Selected Nucleophilic Aromatic Substitution UsingNitroaryls

[0035] Nitroaryls may also undergo transition metal mediated crosscoupling reactions. For example, nitroaryl electrophiles, such asnitroaryl bromides, iodides or triflates, undergo palladium mediatedcross coupling reactions with aryl nucleophiles, such as arylboronicacids (Suzuki reactions, exemplified below), aryltins (Stille reactions)or arylzincs (Negishi reaction) to afford the biaryl (5).

[0036] Either nitroaryls or anilines may be converted into thecorresponding arenesulfonyl chloride (7) on treatment withchlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoridesource, such as KF then affords sulfonyl fluoride (8). Reaction ofsulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the presenceof a fluoride source, such as tris(dimethylamino)sulfoniumdifluorotrimethylsiliconate (TASF) leads to the correspondingtrifluoromethytsulfone (9). Alternatively, sulfonyl chloride 7 may bereduced to the arenethiol (10), for example with zinc amalgum. Reactionof thiol 10 with CHClF₂ in the presence of base gives the difluoromethylmercaptam (11), which may be oxidized to the sulfone (12) with any of avariety of oxidants, including CrO₃-acetic anhydride (Sedova et al. Zh.Org. Khim. 1970, 6, (568).

[0037] As shown in Scheme IV, non-symmetrical urea formation may involvereaction of an aryl isocyanate (14) with an aryl amine (13). Theheteroaryl isocyanate may be synthesized from a heteroaryl amine bytreatment with phosgene or a phosgene equivalent, such astrichloromethyl chloroformate (diphosgene), bis(trichloromethyl)carbonate (triphosgene), or N,N′-carbonyldiimidazole (CDI). Theisocyanate may also be derived from a heterocyclic carboxylic acidderivative, such as an ester, an acid halide or an anhydride by aCurtius-type rearrangement. Thus, reaction of acid derivative 16 with anazide source, followed by rearrangement affords the isocyanate. Thecorresponding carboxylic acid (17) may also be subjected to Curtius-typerearrangements using diphenylphosphoryl azide (DPPA) or a similarreagent.

[0038] Finally, ureas may be further manipulated using methods familiarto those skilled in the art.

[0039] The invention also includes pharmaceutical compositions includinga compound of Formula I, and a physiologically acceptable carrier.

[0040] The compounds may be administered orally, topically,parenterally, by inhalation or spray or rectally in dosage unitformulations. The term ‘administration by injection’ includesintravenous, intramuscular, subcutaneous and parenteral injections, aswell as use of infusion techniques. One or more compounds may be presentin association with one or more non-toxic pharmaceutically acceptablecarriers and if desired other active ingredients.

[0041] Compositions intended for oral use may be prepared according toany suitable method known to the art for the manufacture ofpharmaceutical compositions. Such compositions may contain one or moreagents selected from the group consisting of diluents, sweeteningagents, flavoring agents, coloring agents and preserving agents in orderto provide palatable preparations. Tablets contain the active ingredientin admixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be,for example, inert diluents, such as calcium carbonate, sodiumcarbonate, lactose, calcium phosphate or sodium phosphate; granulatingand disintegrating agents, for example, corn starch, or alginic acid;and binding agents, for example magnesium stearate, stearic acid ortalc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and adsorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. These compounds mayalso be prepared in solid, rapidly released form.

[0042] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

[0043] Aqueous suspensions contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally occurring phosphatide,for example, lecithin, or condensation products or an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolsuch as polyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives, for exampleethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

[0044] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example, sweetening, flavoring andcoloring agents, may also be present.

[0045] The compounds may also be in the form of non-aqueous liquidformulations, e.g., oily suspensions which may be formulated bysuspending the active ingredients in a vegetable oil, for examplearachis oil, olive oil, sesame oil or peanut oil, or in a mineral oilsuch as liquid paraffin. The oily suspensions may contain a thickeningagent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteningagents such as those set forth above, and flavoring agents may be addedto provide palatable oral preparations. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

[0046] Pharmaceutical compositions of the invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

[0047] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents.

[0048] The compounds may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include cocoa butter and polyethylene glycols.

[0049] For all regimens of use disclosed herein for compounds of FormulaI, the daily oral dosage regimen will preferably be from 0.01 to 200mg/Kg of total body weight. The daily dosage for administration byinjection, including intravenous, intramuscular, subcutaneous andparenteral injections, and use of infusion techniques will preferably befrom 0.01 to 200 mg/Kg of total body weight. The daily rectal dosageregime will preferably be from 0.01 to 200 mg/Kg of total body weight.The daily topical dosage regime will preferably be from 0.1 to 200 mgadministered between one to four times daily. The daily inhalationdosage regime will preferably be from 0.01 to 10 mg/Kg of total bodyweight.

[0050] It will be appreciated by those skilled in the art that theparticular method of administration will depend on a variety of factors,all of which are considered routinely when administering therapeutics.It will also be appreciated by one skilled in the art that the specificdose level for a given patient depends on a variety of factors,including specific activity of the compound administered, age, bodyweight, health, sex, diet, time and route of administration, rate ofexcretion, etc. It will be further appreciated by one skilled in the artthat the optimal course of treatment, ie., the mode of treatment and thedaily number of doses of a compound of Formula I or a pharmaceuticallyacceptable salt thereof given for a defined number of days, can beascertained by those skilled in the art using conventional treatmenttests.

[0051] It will be understood, however, that the specific dose level forany particular patient will depend upon a variety of factors, includingthe activity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the condition undergoing therapy.

[0052] The entire enclosure of all applications, patents andpublications cited above and below are hereby incorporated by reference,including provisional application Serial No. 60/115,877, filed Jan. 13,1999 and non-provisional application Ser. No. 09/257,266 filed Feb. 25,1999.

[0053] The compounds can be produced from known compounds (or fromstarting materials which, in turn, can be produced from knowncompounds), e.g., through the general preparative methods shown below.The activity of a given compound to inhibit raf kinase can be routinelyassayed, e.g., according to procedures disclosed below. The followingexamples are for illustrative purposes only and are not intended, norshould they be construed to limit the invention in any way.

EXAMPLES

[0054] All reactions were performed in flame-dried or oven-driedglassware under a positive pressure of dry argon or dry nitrogen, andwere stirred magnetically unless otherwise indicated. Sensitive liquidsand solutions were transferred via syringe or cannula, and introducedinto reaction vessels through rubber septa. Unless otherwise stated, theterm ‘concentration under reduced pressure’ refers to use of a Buchirotary evaporator at approximately 15 mmHg. Unless otherwise stated, theterm ‘under high vacuum’ refers to a vacuum of 0.4-1.0 mmHg.

[0055] All temperatures are reported uncorrected in degrees Celsius (°C.). Unless otherwise indicated, all parts and percentages are byweight.

[0056] Commercial grade reagents and solvents were used without fartherpurification. N-cyclohexyl-N′-(methylpolystyrene)carbodiimide waspurchased from Calbiochem-Novabiochem Corp. 3-tert-Butylaniline,5-tert-butyl-2-methoxyaniline, 4-bromo-3-(trifluoromethyl)aniline,4-chloro-3-(trifluoromethyl)aniline2-methoxy-5-(trifluoromethyl)aniline, 4-tert-butyl-2-nitroaniline,3-amino-2-naphthol, ethyl 4-isocyanatobenzoate,N-acetyl-4-chloro-2-methoxy-5-(trifluoromethyl)aniline and4-chloro-3-(trifluoromethyl)phenyl isocyanate were purchased and usedwithout farther purification. Syntheses of 3-amino-2-methoxyquinoline(E. Cho et al. WO 98/00402; A. Cordi et al. EP 542,609; IBID Bioorg.Med. Chem.. 3, 1995, 129), 4-(3-carbamoylphenoxy)-1-nitrobenzene (K.Ikawa Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b),3-tert-butylphenyl isocyanate (O. Rohr et al. DE 2,436,108) and2-methoxy-5-(trifluoromethyl)phenyl isocyanate (K. Inukai et al. JP42,025,067; IBID Kogyo Kagaku Zasshi 70, 1967, 491) have previously beendescribed.

[0057] Thin-layer chromatography (TLC) was performed using Whatman®pre-coated glass-backed silica gel 60A F-254 250 μm plates.Visualization of plates was effected by one or more of the followingtechniques: (a) ultraviolet illumination, (b) exposure to iodine vapor,(c) immersion of the plate in a 10% solution of phosphomolybdic acid inethanol followed by heating, (d) immersion of the plate in a ceriumsulfate solution followed by heating, and/or (e) immersion of the platein an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed byheating. Column chromatography (flash chromatography) was performedusing 230-400 mesh EM Science® silica gel.

[0058] Melting points (mp) were determined using a Thomas-Hoover meltingpoint apparatus or a Mettler FP66 automated melting point apparatus andare uncorrected. Fourier transform infrared spectra were obtained usinga Mattson 4020 Galaxy Series spectrophotometer. Proton (¹H) nuclearmagnetic resonance (NMR) spectra were measured with a General ElectricGN-Omega 300 (300 MHz) spectrometer with either Me₄Si (δ0.00) orresidual protonated solvent (CHCl₃ δ7.26; MeOH δ3.30; DMSO δ2.49) asstandard. Carbon (¹³C) NMR spectra were measured with a General ElectricGN-Omega 300 (75 MHz) spectrometer with solvent (CDCl₃ δ77.0; MeOD-d₃;δ49.0; DMSO-d₆ δ39.5) as standard. Low resolution mass spectra (MS) andhigh resolution mass spectra (HRMS) were either obtained as electronimpact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra.Electron impact mass spectra (EI-MS) were obtained with a HewlettPackard 5989A mass spectrometer equipped with a Vacumetrics DesorptionChemical Ionization Probe for sample introduction. The ion source wasmaintained at 250° C. Electron impact ionization was performed withelectron energy of 70 eV and a trap current of 300 μA. Liquid-cesiumsecondary ion mass spectra (FAB-MS), an updated version of fast atombombardment were obtained using a Kratos Concept 1-H spectrometer.Chemical ionization mass spectra (CI-MS) were obtained using a HewlettPackard MS-Engine (5989A) with methane or ammonia as the reagent gas(1×10⁻⁴ torr to 2.5×10⁻⁴ torr). The direct insertion desorption chemicalionization (DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 ampsin 10 sec and held at 10 amps until all traces of the sample disappeared(˜1-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan.HPLC—electrospray mass spectra (HPLC ES-MS) were obtained using aHewlett-Packard 1100 HPLC equipped with a quaternary pump, a variablewavelength detector, a C-18 column, and a Finnigan LCQ ion trap massspectrometer with electrospray ionization. Spectra were scanned from120-800 amu using a variable ion time according to the number of ions inthe source. Gas chromatography—ion selective mass spectra (GC-MS) wereobtained with a Hewlett Packard 5890 gas chromatograph equipped with anHP-1 methyl silicone column (0.33 mM coating; 25 m×0.2 mm) and a HewlettPackard 5971 Mass Selective Detector (ionization energy 70 eV).Elemental analyses are conducted by Robertson Microlit Labs, MadisonN.J.

[0059] All compounds displayed NMR spectra, LRMS and either elementalanalysis or HRMS consistent with assigned structures. List ofAbbreviations and Acronyms: AcOH acetic acid anh anhydrous atmatmosphere(s) BOC tert-butoxycarbonyl CDI 1,1′-carbonyl diimidazole concconcentrated d day(s) dec decomposition DMAC N,N-dimethylacetamide DMPU1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMFN,N-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphorylazide EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EtOAc ethylacetate EtOH ethanol (100%) Et₂O diethyl ether Et₃N triethylamine hhour(s) HOBT 1-hydroxybenzotriazole m- 3-chloroperoxybenzoic acid CPBAMeOH methanol pet. petroleum ether (boiling range 30-60° C.) ether temp.temperature THF tetrahydrofuran TFA trifluoroAcOH Tftrifluoromethanesulfonyl A. General Methods for Synthesis of SubstitutedAnilines Al. General Method for Aryl Amine Formation via Ether FormationFollowed by Ester Saponification, Curtius Rearrangement, and CarbamateDeprotection. Synthesis of 2-Amino-3- methoxynaphthalene.

[0060]

[0061] Step 1. Methyl 3-methoxy-2-naphthoate

[0062] A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) andK₂CO₃ (7.96 g, 57.6 mmol) in DMF (200 mL) was stirred at room temp. for15 min., then treated with iodomethane (3.43 mL, 55.1 mmol). The mixturewas allowed to stir at room temp. overnight, then was treated with water(200 mL). The resulting mixture was extracted with EtOAc (2×200 mL). Thecombined organic layers were washed with a saturated NaCl solution (100mL), dried (MgSO₄), concentrated under reduced pressure (approximately0.4 mmHg overnight) to give methyl 3-methoxy-2-naphthoate as an amberoil (10.30 g): ¹H-NMR (DMSO-d₆) δ2.70 (s, 3H), 2.85 (s, 3H), 7.38 (appt, J=8.09 Hz, 1H), 7.44 (s, 1H), 7.53 (app t, J=8.09 Hz, 1H), 7.84 (d,J=8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).

[0063] Step 2. 3-Methoxy-2-naphthoic acid

[0064] A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol)and water (10 mL) in MeOH (100 mL) at room temp. was treated with a 1 NNaOH solution (33.4 mL, 33.4 mmol). The mixture was heated at the refluxtemp. for 3 h, cooled to room temp., and made acidic with a 10% citricacid solution. The resulting solution was extracted with EtOAc (2×100mL). The combined organic layers were washed with a saturated NaClsolution, dried (MgSO₄) and concentrated under reduced pressure. Theresidue was triturated with hexane then washed several times with hexaneto give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%):¹H-NMR (DMSO-d₆) δ3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H),7.83 (d, J=8.09 Hz, 1H), 7.91 (d, J=8.09 Hz, 1H), 8.19 (s, 1H), 12.83(br s, 1H).

[0065] Step 3. 2-(N-(Carbobenzyloxy)amino-3-methoxynaphthalene

[0066] A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) andEt₃N (2.59 mL, 18.6 mmol) in anh toluene (70 mL) was stirred at roomtemp. for 15 min., then treated with a solution of DPPA (5.12 g, 18.6mmol) in toluene (10 mL) via pipette. The resulting mixture was heatedat 80° C. for 2 h. After cooling the mixture to room temp., benzylalcohol (2.06 mL, 20 mmol) was added via syringe. The mixture was thenwarmed to 80° C. overnight. The resulting mixture was cooled to roomtemp., quenched with a 10% citric acid solution, and extracted withEtOAc (2×100 mL). The combined organic layers were washed with asaturated NaCl solution, dried (MgSO₄) and concentrated under reducedpressure. The residue was purified by column chromatography (14%EtOAc/86% hexane) to give2-(N-(carbobenzyloxy)amino-3-methoxynaphthalene as a pale yellow oil(5.1 g, 100%): ¹H-NMR (DMSO-d₆) δ3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44(m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, 1H), 8.76 (s, 1H).

[0067] Step 4. 2-Amino-3-methoxynaphthalene

[0068] A slurry of 2-(N-(carbobenzyloxy)amino-3-methoxynaphthalene (5.0g, 16.3 mmol) and 10% Pd/C (0.5 g) in EtOAc (70 mL) was maintained undera H₂ atm (balloon) at room temp. overnight. The resulting mixture wasfiltered through Celite® and concentrated under reduced pressure to give2-amino-3-methoxynaphthalene as a pale pink powder (2.40 g, 85%): ¹H-NMR(DMSO-d₆) δ3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, J=8.0Hz, 1H), 7.56 (d, J=8.0 Hz, 1H); EI-MS m/z 173 (M⁺).

A2. Synthesis of ω-Carbamyl Anilines via Formation of a CarbamylpyridineFollowed by Nucleophilic Coupling with an Aryl Amine. Synthesis of4-(2-N-Methylcarbamyl-4-pyridyloxy)aniline

[0069]

[0070] Step 1a. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide viathe Menisci Reaction

[0071] Caution: this is a highly hazardous, potentially explosivereaction. To a stirring solution of 4-chloropyridine (10.0 g) inN-methylformamide (250 mL) at room temp. was added conc. H₂SO₄ (3.55 mL)to generate an exotherm. To this mixture was added H₂O₂ (30% wt in H₂O,17 mL) followed by FeSO₄.7H₂O (0.56 g) to generate another exotherm. Theresulting mixture was stirred in the dark at room temp. for 1 h, thenwarmed slowly over 4 h to 45° C. When bubbling had subsided, thereaction was heated at 60° C. for 16 h. The resulting opaque brownsolution was diluted with H₂O (700 mL) followed by a 10% NaOH solution(250 mL). The resulting mixture was extracted with EtOAc (3×500 mL). Theorganic phases were washed separately with a saturated NaCl solution(3×150 mL), then they were combined, dried (MgSO₄) and filtered througha pad of silica gel with the aid of EtOAc. The resulting brown oil waspurified by column chromatography (gradient from 50% EtOAc/50% hexane to80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0° C.over 72 h to give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g,5.3%): TLC (50% EtOAc/50% hexane) R_(f) 0.50; ¹H NMR (CDCl₃) δ3.04 (d,J=5.1 Hz, 3H), 7.43 (dd, J=5.4, 2.4 Hz, 1H), 7.96 (br s, 1H), 8.12 (s,1H), 8.44 (d, J=5.1 Hz, 1H); CI-MS m/z 171 ((M+H)⁺).

[0072] Step 1b. Synthesis of 4-chloropyridine-2-carbonyl Chloride HClSalt via Picolinic Acid

[0073] Anhydrous DMF (6.0 mL) was slowly added to SOCl₂ (180 mL) between40° and 50° C. The solution was stirred in that temperature range for 10min. then picolinic acid (60.0 g, 487 mmol) was added in portions over30 min. The resulting solution was heated at 72° C. (vigorous SO₂evolution) for 16 h to generate a yellow solid precipitate. Theresulting mixture was cooled to room temp., diluted with toluene (500mL) and concentrated to 200 mL. The toluene addition/concentrationprocess was repeated twice. The resulting nearly dry residue wasfiltered and the solids were washed with toluene (2×200 mL) and driedunder high vacuum for 4 h to afford 4-chloropyridine-2-carbonyl chlorideHCl salt as a yellow-orange solid (92.0 g, 89%).

[0074] Step 2. Synthesis of methyl 4-chloropyridine-2-carboxylate HClSalt

[0075] Anh DMF (10.0 mL) was slowly added to SOCl₂ (300 mL) at 40-48° C.The solution was stirred at that temp. range for 10 min., then picolinicacid (100 g, 812 mmol) was added over 30 min. The resulting solution washeated at 72° C. (vigorous SO₂ evolution) for 16 h to generate a yellowsolid. The resulting mixture was cooled to room temp., diluted withtoluene (500 mL) and concentrated to 200 mL. The tolueneaddition/concentration process was repeated twice. The resulting nearlydry residue was filtered, and the solids were washed with toluene (50mL) and dried under high vacuum for 4 hours to afford4-chloropyridine-2-carbonyl chloride HCl salt as an off-white solid(27.2 g, 16%). This material was set aside.

[0076] The red filtrate was added to MeOH (200 mL) at a rate which keptthe internal temperature below 55° C. The contents were stirred at roomtemp. for 45 min., cooled to 5° C. and treated with Et₂O (200 mL)dropwise. The resulting solids were filtered, washed with Et₂O (200 mL)and dried under reduced pressure at 35° C. to provide methyl4-chloropyridine-2-carboxylate HCl salt as a white solid (110 g, 65%):mp 108-112° C.; ¹H-NMR (DMSO-d₆) δ3.88 (s, 3H); 7.82 (dd, J=5.5, 2.2 Hz,1H); 8.08 (d, J=2.2 Hz, 1H); 8.68 (d, J=5.5 Hz, 1H); 10.68 (br s, 1H);HPLC ES-MS m/z 172 ((M+H)⁺).

[0077] Step 3a. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamidefrom Methyl 4-chloropyridine-2-carboxylate

[0078] A suspension of methyl 4-chloropyridine-2-carboxylate HCl salt(89.0 g, 428 mmol) in MeOH (75 mL) at 0° C. was treated with a 2.0 Mmethylamine solution in THF (1 L) at a rate which kept the internaltemp. below 5° C. The resulting mixture was stored at 3° C. for 5 h,then concentrated under reduced pressure. The resulting solids weresuspended in EtOAc (1 L) and filtered. The filtrate was washed with asaturated NaCl solution (500 mL), dried (Na₂SO₄) and concentrated underreduced pressure to afford 4-chloro-N-methyl-2-pyridinecarboxamide aspale-yellow crystals (71.2 g, 97%): mp 41-43° C.; ¹H-NMR (DMSO-d₆) δ2.81(s, 3H), 7.74 (dd, J=5.1, 2.2 Hz, 1H), 8.00 (d, J=2.2, 1H), 8.61 (d,J=5.1 Hz, 1H), 8.85 (br d, 1H); CI-MS m/z 171 ((M+H)⁺).

[0079] Step 3b. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamidefrom 4-chloropyridine-2-carbonyl Chloride

[0080] 4-Chloropyridine-2-carbonyl chloride HCl salt (7.0 g, 32.95 mmol)was added in portions to a mixture of a 2.0 M methylamine solution inTHF (100 mL) and MeOH (20 mL) at 0 ° C. The resulting mixture was storedat 3° C. for 4 h, then concentrated under reduced pressure. Theresulting nearly dry solids were suspended in EtOAc (100 mL) andfiltered. The filtrate was washed with a saturated NaCl solution (2×100mL), dried (Na₂SO₄) and concentrated under reduced pressure to provide4-chloro-N-methyl-2-pyridinecarboxamide as a yellow, crystalline solid(4.95 g, 88%): mp 37-40° C.

[0081] Step 4. Synthesis of4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline

[0082] A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DNMF (150mL) was treated with potassium tert-butoxide (10.29 g, 91.7 mmol), andthe reddish-brown mixture was stirred at room temp. for 2 h. Thecontents were treated with 4-chloro-N-methyl-2-pyridinecarboxamide (15.0g, 87.9 mmol) and K₂CO₃ (6.50 g, 47.0 mmol) and then heated at 80° C.for 8 h. The mixture was cooled to room temp. and separated betweenEtOAc (500 mL) and a saturated NaCl solution (500 mL). The aqueous phasewas back-extracted with EtOAc (300 mL). The combined organic layers werewashed with a saturated NaCl solution (4×1000 mL), dried (Na₂SO₄) andconcentrated under reduced pressure. The resulting solids were driedunder reduced pressure at 35° C. for 3 h to afford4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline as a light-brown solid17.9 g, 84%): ¹H-NMR (DMSO-d₆) δ2.77 (d, J=4.8 Hz, 3H), 5.17 (br s, 2H),6.64, 6.86 (AA′BB′ quartet, J=8.4 Hz, 4H), 7.06 (dd, J=5.5, 2.5 Hz, 1H),7.33 (d, J=2.5 Hz, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.73 (br d, 1H); HPLCES-MS m/z 244 ((M+H)⁺).

A3. General Method for the Synthesis of Anilines by NucleophilicAromatic Addition Followed by Nitroarene Reduction. Synthesis of5-(4-Aminophenoxy)isoindoline-1,3-dione

[0083]

[0084] Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione

[0085] To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc.AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45mmol). The resulting mixture was heated at 120° C. for 45 min., then theclear, bright yellow mixture was heated at 160° C. for 2 h. Theresulting mixture was maintained at 160° C. and was concentrated toapproximately 15 mL, then was cooled to room temp. and adjusted pH 10with a 1N NaOH solution. This mixture was cooled to 0° C. and slowlyacidified to pH 5 using a 1N HCl solution. The resultant precipitate wascollected by filtration and dried under reduced pressure to yield5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24g, 72%): ¹H NMR (DMSO-d₆) δ7.00-7.03 (m, 2H), 7.56 (d, J=9.3 Hz, 1H).

[0086] Step 2. Synthesis of 5-(4-nitrophenoxy)isoindoline-1,3-dione

[0087] To a stirring slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at0° C. was added a solution of 5-hydroxyisoindoline-1,3-dione (3.2 g,19.6 mmol) in DMF (40 mL) dropwise. The bright yellow-green mixture wasallowed to return to room temp. and was stirred for 1 h, then1-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4portions. The resulting mixture was heated at 70° C. overnight, thencooled to room temp. and diluted slowly with water (150 mL), andextracted with EtOAc (2×100 mL). The combined organic layers were dried(MgSO₄) and concentrated under reduced pressure to give5-(4-nitrophenoxy)isoindoline-1,3-dione as a yellow solid (3.3 g, 62%):TLC (30% EtOAc/70% hexane) R_(f) 0.28; 1H NMR (DMSO-d₆) 67 7.32 (d, J=12Hz, 2H), 7.52-7.57 (m, 2H), 7.89(d, J=7.8 Hz, 1H), 8.29 (d, J=9 Hz, 2H),11.43 (br s, 1H); CI-MS m/z 285 ((M+H)⁺, 100%).

[0088] Step 3. Synthesis of 5-(4-aminophenoxy)isoindoline-1,3-dione

[0089] A solution of 5-(4-nitrophenoxy)isoindoline-1,3-dione (0.6 g,2.11 mmol) in conc. AcOH (12 mL) and water (0.1 mL) was stirred understream of argon while iron powder (0.59 g, 55.9 mmol) was added slowly.This mixture stirred at room temp. for 72 h, then was diluted with water(25 mL) and extracted with EtOAc (3×50 mL). The combined organic layerswere dried (MgSO₄) and concentrated under reduced pressure to give5-(4-aminophenoxy)isoindoline-1,3-dione as a brownish solid (0.4 g,75%): TLC (50% EtOAc/50% hexane) R_(f) 0.27; ¹H NMR (DMSO-d₆) δ5.14 (brs, 2H), 6.62 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 7.03 (d, J=2.1Hz, 1H), 7.23 (dd, 1H), 7.75 (d, J=8.4 Hz, 1H), 11.02 (s, 1H); HPLCES-MS m/z 255 ((M+H)⁺, 100%).

A4. General Method for the Synthesis of Pyrrolylanilines. Synthesis of5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline

[0090]

[0091] Step 1. Synthesis of1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole

[0092] To a stirring solution of 2-nitro-4-tert-butylaniline (0.5 g,2.57 mmol) in cyclohexane (10 mL) was added AcOH (0.1 mL) andacetonylacetone (0.299 g, 2.63 mmol) via syringe. The reaction mixturewas heated at 120° C. for 72 h with azeotropic removal of volatiles. Thereaction mixture was cooled to room temp., diluted with CH₂Cl₂ (10 mL)and sequentially washed with a 1N HCl solution (15 mL), a 1N NaOHsolution (15 mL) and a saturated NaCl solution (15 mL), dried (MgSO₄)and concentrated under reduced pressure. The resulting orange-brownsolids were purified via column chromatography (60 g SiO₂; gradient from6% EtOAc/94% hexane to 25% EtOAc/75% hexane) to give1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole as an orange-yellowsolid (0.34 g, 49%): TLC (15% EtOAc/85% hexane) R_(f) 0.67; ¹H NMR(CDCl₃) d 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, 1H),7.62 (dd, 1H), 7.88 (d, J=2.4 Hz, 1H); CI-MS m/z 273 ((M+H)⁺, 50%).

[0093] Step 2. Synthesis of 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline

[0094] A slurry of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole(0.341 g, 1.25 mmol), 10%Pd/C (0.056 g) and EtOAc (50 mL) under an H₂atmosphere (balloon) was stirred for 72 h, then filtered through a padof Celite®. The filtrate was concentrated under reduced pressure to give5-tert-butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish solids (0.30g, 99%): TLC (10% EtOAc/90% hexane) R_(f) 0.43; ¹H NMR (CDCl₃) δ1.28 (s,9H), 1.87-1.91 (m, 8H), 5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s,1H).

A5. General Method for the Synthesis of Anilines from Anilines byNucleophilic Aromatic Substitution. Synthesis of4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline HCl Salt

[0095]

[0096] A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in drydimethylacetamide (75 mL) was treated with potassium tert-butoxide(10.86 g, 96.77 mmol) and the black mixture was stirred at room temp.until the flask had reached room temp. The contents were then treatedwith 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52g, 44.2 mmol) and heated at 110° C. for 8 h. The mixture was cooled toroom temp. and diluted with water (75 mL). The organic layer wasextracted with EtOAc (5×100 mL). The combined organic layers were washedwith a saturated NaCl solution (200 mL), dried (MgSO₄) and concentratedunder reduced pressure. The residual black oil was treated with Et₂O (50mL) and sonicated. The solution was then treated with HCl (1 M in Et₂O;100 mL) and stirred at room temp. for 5 min. The resulting dark pinksolid (7.04 g, 24.1 mmol) was removed by filtration from solution andstored under anaerobic conditions at 0° C. prior to use: ¹H NMR(DMSO-d₆) δ2.41 (s, 3H), 2.78 (d, J=4.4 Hz, 3H), 4.93 (br s, 2H), 7.19(dd, J=8.5, 2.6 Hz, 1H), 7.23 (dd, J=5.5, 2.6 Hz, 1H), 7.26 (d, J=2.6Hz, 1H), 7.55 (d, J=2.6 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 8.55 (d, J=5.9Hz, 1H), 8.99 (q, J=4.8 Hz, 1H).

A6. General Method for the Synthesis of Anilines from Hydroxyanilines byN-Protection, Nucleophilic Aromatric Substitution and Deprotection.Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline

[0097]

[0098] Step 1: Synthesis of3-Chloro-4-(2,2,2-trifluoroacetylamino)phenol

[0099] Iron (3.24 g, 58.00 mmol) was added to stirring TFA (200 mL). Tothis slurry was added 2-chloro-4-nitrophenol (10.0 g, 58.0 mmol) andtrifluoroacetic anhydride (20 mL). This gray slurry was stirred at roomtemp. for 6 d. The iron was filtered from solution and the remainingmaterial was concentrated under reduced pressure. The resulting graysolid was dissolved in water (20 mL). To the resulting yellow solutionwas added a saturated NaHCO₃ solution (50 mL). The solid whichprecipitated from solution was removed. The filtrate was slowly quenchedwith the sodium bicarbonate solution until the product visibly separatedfrom solution (determined was using a mini work-up vial). The slightlycloudy yellow solution was extracted with EtOAc (3×125 mL). The combinedorganic layers were washed with a saturated NaCl solution (125 mL),dried (MgSO₄) and concentrated under reduced pressure. The ¹H NMR(DMSO-d₆) indicated a 1:1 ratio of the nitrophenol starting material andthe intended product 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol. Thecrude material was taken on to the next step without furtherpurification.

[0100] Step 2: Synthesis of4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl(222-trifluoro)acetamide

[0101] A solution of crude 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol(5.62 g, 23.46 mmol) in dry dimethylacetamide (50 mL) was treated withpotassium tert-butoxide (5.16 g, 45.98 mmol) and the brownish blackmixture was stirred at room temp. until the flask had cooled to roomtemp. The resulting mixture was treated with4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 1.99 g,11.7 mmol) and heated at 100° C. under argon for 4 d. The black reactionmixture was cooled to room temp. and then poured into cold water (100mL). The mixture was extracted with EtOAc (3×75 mL) and the combinedorganic layers were concentrated under reduced pressure. The residualbrown oil was purified by column chromatography (gradient from 20%EtOAc/pet. ether to 40% EtOAc/pet. ether) to yield4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl(222-trifluoro)acetamide as a yellow solid (8.59 g, 23.0 mmol).

[0102] Step 3. Synthesis of4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline

[0103] A solution of crude4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl(222-trifluoro)acetamide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL)was treated with a 1N NaOH solution (20 mL). This brown solution wasallowed to stir for 8 h. To this solution was added EtOAc (40 mL). Thegreen organic layer was extracted with EtOAc (3×40 mL) and the solventwas concentrated to yield4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline as a green oilthat solidified upon standing (2.86 g, 10.30 mmol): ¹H NMR (DMSO-d₆)δ2.77 (d, J=4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, J=8.5, 2.6 Hz, 1H),6.76 (d, J=2.6 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 7.07 (dd, J=5.5, 2.6,Hz, 1H), 7.27 (d, J=2.6 Hz, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.75 (q, J=4.8,1H).

A7. General Method for the Deprotection of an Acylated Aniline.Synthesis of 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline

[0104]

[0105] A suspension of 3-chloro-6-(N-acetyl)-4-(trifluoromethyl)anisole(4.00 g, 14.95 mmol) in a 6M HCl solution (24 mL) was heated at thereflux temp. for 1 h. The resulting solution was allowed to cool to roomtemp. during which time it solidified slightly. The resulting mixturewas diluted with water (20 mL) then treated with a combination of solidNaOH and a saturated NaHCO₃ solution until the solution was basic. Theorganic layer was extracted with CH₂Cl₂ (3×50 mL). The combined organicswere dried (MgSO₄) and concentrated under reduced pressure to yield4-chloro-2-methoxy-5-(trifluoromethyl)aniline as a brown oil (3.20 g,14.2 mmol): ¹H NMR (DMSO-d₆) δ3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).

A8. General Method for Synthesis of ω-Alkoxy-ω-carboxyphenyl Anilines.Synthesis of 4-(3-(N-Methylcarbamoly)-4-methoxyphenoxy)aniline

[0106]

[0107] Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene:

[0108] To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-1-nitrobenzene(prepared from 2,5-dihydroxybenzoic acid in a manner analogous to thatdescribed in Method A13, Step 1, 12 mmol) in acetone (50 mL) was addedK₂CO₃ (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture washeated at the reflux temp. overnight, then cooled to room temp. andfiltered through a pad of Celite®. The resulting solution wasconcentrated under reduced pressure, absorbed onto SiO₂, and purified bycolumn chromatography (50% EtOAc/50% hexane) to give4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene as a yellow powder(3 g): mp 115-118° C.

[0109] Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-1-nitrobenzene:

[0110] A mixture of4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene (1.2 g), KOH (0.33g) and water (5 mL) in MeOH (45 mL) was stirred at room temp. overnightand then heated at the reflux temp. for 4 h. The resulting mixture wascooled to room temp. and concentrated under reduced pressure. Theresidue was dissolved in water (50 mL), and the aqueous mixture was madeacidic with a 1N HCl solution. The resulting mixture was extracted withEtOAc (50 mL). The organic layer was dried (MgSO₄) and concentratedunder reduced pressure to give4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (1.04 g).

[0111] Step 3.4-(3-(N-Methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene:

[0112] To a solution of 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene(0.50 g, 1.75 mmol) in CH₂Cl₂ (12 mL) was added SOCl₂ (0.64 mL, 8.77mmol) in portions. The resulting solution was heated at the reflux temp.for 18 h, cooled to room temp., and concentrated under reduced pressure.The resulting yellow solids were dissolved in CH₂Cl₂ (3 mL) then theresulting solution was treated with a methylamine solution (2.0 M inTHF, 3.5 mL, 7.02 mmol) in portions (CAUTION: gas evolution), andstirred at room temp. for 4 h. The resulting mixture was treated with a1N NaOH solution, then extracted with CH₂Cl₂ (25 mL). The organic layerwas dried (Na₂SO₄) and concentrated under reduced pressure to give4-(3-(N-methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene as a yellowsolid (0.50 g, 95%).

[0113] Step 4. 4-(3-(N-Methylcarbamoly)-4-methoxyphenoxy)aniline:

[0114] A slurry of4-(3-(N-methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene (0.78 g, 2.60mmol) and 10% Pd/C (0.20 g) in EtOH (55 mL) was stirred under 1 atm ofH₂ (balloon) for 2.5 d, then was filtered through a pad of Celite®. Theresulting solution was concentrated under reduced pressure to afford4-(3-(N-methylcarbamoly)-4-methoxyphenoxy)aniline as an off-white solid(0.68 g, 96%): TLC (0.1% Et₃N/99.9% EtOAc) R_(f) 0.36.

A9. General Method for Preparation of ω-Alkylphthalimide-containingAnilines. Synthesis of 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione

[0115]

[0116] Step 1. Synthesis of5-(4-Nitrophenoxy)-2-methylisoindoline-1,3-dione:

[0117] A slurry of 5-(4-nitrophenoxy)isoindoline-1,3-dione (A3 Step 2;1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 mL) was stirredat room temp. for 1 h, then treated with methyl iodide (0.3 mL, 4.57mmol). The resulting mixture was stirred at room temp. overnight, thenwas cooled to ° C. and treated with water (10 mL). The resulting solidswere collected and dried under reduced pressure to give5-(4-nitrophenoxy)-2-methylisoindoline-1,3-dione as a bright yellowsolid (0.87 g, 83%): TLC (35% EtOAc/65% hexane) R_(f) 0.61.

[0118] Step 2. Synthesis of5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione:

[0119] A slurry of nitrophenoxy)-2-methylisoindoline-1,3-dione (0.87 g,2.78 mmol) and 10% Pd/C (0.10 g) in MeOH was stirred under 1 atm of H₂(balloon) overnight. The resulting mixture was filtered through a pad ofCelite® and concentrated under reduced pressure. The resulting yellowsolids were dissolved in EtOAc (3 mL) and filtered through a plug ofSiO₂ (60% EtOAc/40% hexane) to afford5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione as a yellow solid (0.67g, 86%): TLC (40% EtOAc/60% hexane) R_(f) 0.27.

A10. General Method for Synthesis of ω-Carbamoylaryl Anilines ThroughReaction of ω-Alkoxycarbonylaryl Precursors with Amines. Synthesis of4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline

[0120]

[0121] Step 1. Synthesis of4-Chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine

[0122] To a solution of methyl 4-chloropyridine-2-carboxylate HCl salt(Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 mL) was added4-(2-aminoethyl)morpholine (2.55 mL, 19.4 mmol) dropwise and theresulting solution was heated at the reflux temp. for 20 h, cooled toroom temp., and treated with water (50 mL). The resulting mixture wasextracted with EtOAc (50 mL). The organic layer was dried (MgSO₄) andconcentrated under reduced pressure to afford4-chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow oil(1.25 g, 95%): TLC (10% MeOH/90% EtOAc) R_(f) 0.50.

[0123] Step 2. Synthesis of4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline.

[0124] A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassiumtert-butoxide (0.53 g, 4.75 mmol) in DMF (8 mL) was stirred at roomtemp. for 2 h, then was sequentially treated with4-chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine (1.22 g, 4.52mmol) and K₂CO₃ (0.31 g, 2.26 mmol). The resulting mixture was heated at75° C. overnight, cooled to room temp., and separated between EtOAc (25mL) and a saturated NaCl solution (25 mL). The aqueous layer was backextracted with EtOAc (25 mL). The combined organic layers were washedwith a saturated NaCl solution (3×25 mL) and concentrated under reducedpressure. The resulting brown solids were purified by columnchromatography (58 g; gradient from 100% EtOAc to 25% MeOH/75% EtOAc) toafford 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline (1.0g, 65%): TLC (10% MeOH/90% EtOAc) R_(f) 0.32.

A11. General Method for the Reduction of Nitroarenes to Arylamines.Synthesis of 4-(3-Carboxyphenoxy)aniline

[0125]

[0126] A slurry of 4-(3-carboxyphenoxy)-1-nitrobenzene (5.38 g, 20.7mmol) and 10% Pd/C (0.50 g) in MeOH (120 mL) was stirred under an H₂atmosphere (balloon) for 2 d. The resulting mixture was filtered througha pad of Celite®, then concentrated under reduced pressure to afford4-(3-carboxyphenoxy)aniline as a brown solid (2.26 g, 48%): TLC (10%MeOH/90% CH₂Cl₂) R_(f) 0.44 (streaking).

A12. General Method for the Synthesis of Isoindolinone-ContainingAnilines. Synthesis of 4-(1-Oxoisoindolin-5-yloxy)aniline

[0127]

[0128] Step 1. Synthesis of 5-hydroxyisoindolin-1-one

[0129] To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH(500 mL) was slowly added zinc dust (47.6 g, 729 mmol) in portions, thenthe mixture was heated at the reflux temp. for 40 min., filtered hot,and concentrated under reduced pressure. The reaction was repeated onthe same scale and the combined oily residue was purified by columnchromatography (1.1 Kg SiO₂; gradient from 60% EtOAc/40% hexane to 25%MeOH/75% EtOAc) to give 5-hydroxyisoindolin-1-one (3.77 g): TLC (100%EtOAc) R_(f) 0.17; HPLC ES-MS m/z 150 ((M+H)⁺).

[0130] Step 2. Synthesis of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene

[0131] To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0° C. was added5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in portions. The resultingslurry was allowed to warm to room temp. and was stirred for 45 min.,then 4-fluoro-1-nitrobenzene was added and then mixture was heated at70° C. for 3 h. The mixture was cooled to 0° C. and treated with waterdropwise until a precipitate formed. The resulting solids were collectedto give 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene as a dark yellow solid(3.23 g, 89%): TLC (100% EtOAc) R_(f) 0.35.

[0132] Step 3. Synthesis of 4-(1-oxoisoindolin-5-yloxy)aniline

[0133] A slurry of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene (2.12 g,7.8 mmol) and 10% Pd/C (0.20 g) in EtOH (50 mL) was stirred under an H₂atmosphere (balloon) for 4 h, then filtered through a pad of Celite®.The filtrate was concentrated under reduced pressure to afford4-(1-oxoisoindolin-5-yloxy)aniline as a dark yellow solid: TLC (100%EtOAc) R_(f) 0.15.

A13. General Method for the Synthesis of ω-Carbamoyl Anilines viaEDCI-Mediated Amide Formation Followed by Nitroarene Reduction Synthesisof 4-(3-N-Methylcarbamoylphenoxy)aniline.

[0134]

[0135] Step 1. Synthesis of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene

[0136] A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl3-hydroxybenzoate 25 g, 150 mmol) and K₂CO₃ (41 g, 300 mmol) in DMF (125mL) was heated at the reflux temp. overnight, cooled to room temp. andtreated with water (250 mL). The resulting mixture was extracted withEtOAc (3×150 mL). The combined organic phases were sequentially washedwith water (3×100 mL) and a saturated NaCl solution (2×100 mL), dried(Na₂SO₄) and concentrated under reduced pressure. The residue waspurified by column chromatography (10% EtOAc/90% hexane) to afford4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene as an oil (38 g).

[0137] Step 2. Synthesis of 4-(3-carboxyphenoxy)-1-nitrobenzene

[0138] To a vigorously stirred mixture of4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene (5.14 g, 17.9 mmol) in a 3:1THF/water solution (75 mL) was added a solution LiOH.H₂O (1.50 g, 35.8mmol) in water (36 mL). The resulting mixture was heated at 50° C.overnight, then cooled to room temp., concentrated under reducedpressure, and adjusted to pH 2 with a 1M HCl solution. The resultingbright yellow solids were removed by filtration and washed with hexaneto give 4-(3-carboxyphenoxy)-1-nitrobenzene (4.40 g, 95%).

[0139] Step 3. Synthesis of4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene

[0140] A mixture of 4-(3-carboxyphenoxy)-1-nitrobenzene (3.72 g, 14.4mmol), EDCI.HCl (3.63 g, 18.6 mmol), N-methylmorpholine (1.6 mL, 14.5mmol) and methylamine (2.0 M in THF; 8 mL, 16 mmol) in CH₂Cl₂ (45 mL)was stirred at room temp. for 3 d, then concentrated under reducedpressure. The residue was dissolved in EtOAc (50 mL) and the resultingmixture was extracted with a 1M HCl solution (50 mL). The aqueous layerwas back-extracted with EtOAc (2×50 mL). The combined organic phaseswere washed with a saturated NaCl solution (50 mL), dried (Na₂SO₄), andconcentrated under reduced pressure to give4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene as an oil (1.89 g).

[0141] Step 4. Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy)aniline

[0142] A slurry of 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene (1.89g, 6.95 mmol) and 5% Pd/C (0.24 g) in EtOAc (20 mL) was stirred under anH₂ atm (balloon) overnight. The resulting mixture was filtered through apad of Celite® and concentrated under reduced pressure. The residue waspurified by column chromatography (5% MeOH/95% CH₂Cl₂). The resultingoil solidified under vacuum overnight to give4-(3-(N-methylcarbamoyl)phenoxy)aniline as a yellow solid (0.95 g, 56%).

A14. General Method for the Synthesis of ω-Carbamoyl Anilines viaEDCI-Mediated Amide Formation Followed by Nitroarene Reduction.Synthesis of 4-3-(5-Methylcarbamoyl)pyridyloxy)aniline

[0143]

[0144] Step 1. Synthesis of4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene

[0145] To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added asolution of methyl 5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10mL). The resulting mixture was added to a solution of4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and theresulting mixture was heated at 70° C. overnight, cooled to room temp.,and treated with MeOH (5 mL) followed by water (50 mL). The resultingmixture was extracted with EtOAc (100 mL). The organic phase wasconcentrated under reduced pressure. The residue was purified by columnchromatography (30% EtOAc/70% hexane) to afford4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g).

[0146] Step 2. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline

[0147] A slurry of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene(0.60 g, 2.20 mmol) and 10% Pd/C in MeOH/EtOAc was stirred under an H₂atmosphere (balloon) for 72 h. The resulting mixture was filtered andthe filtrate was concentrated under reduced pressure. The residue waspurified by column chromatography (gradient from 10% EtOAc/90% hexane to30% EtOAc/70% hexane to 50% EtOAc/50% hexane) to afford4-(3-(5-methoxycarbonyl)pyridyloxy)aniline (0.28 g, 60%): ¹H NMR (CDCl₃)δ3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (, 1H), 8.51 (d, 1H),8.87 (d, 1H).

A15. Synthesis of an Aniline via Electrophilic Nitration Followed byReduction. Synthesis of 4-(3-Methylsulfamoylphenoxy)aniline

[0148]

[0149] Step 1. Synthesis of N-methyl-3-bromobenzenesulfonamide

[0150] To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2mmol) in THF (15 mL) at 0° C. was added methylamine (2.0 M in THF; 28mL, 56 mmol). The resulting solution was allowed to warm to room temp.and was stirred at room temp. overnight. The resulting mixture wasseparated between EtOAc (25 mL) and a 1 M HCl solution (25 mL). Theaqueous phase was back-extracted with EtOAc (2×25 mL). The combinedorganic phases were sequentially washed with water (2×25 mL) and asaturated NaCl solution (25 mL), dried (MgSO₄) and concentrated underreduced pressure to give N-methyl-3-bromobenzenesulfonamide as a whitesolid (2.8 g, 99%).

[0151] Step 2. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)benzene

[0152] To a slurry of phenol (1.9 g, 20 mmol), K₂CO₃ (6.0 g, 40 mmol),and CuI (4 g, 20 mmol) in DMF (25 mL) was addedN-methyl-3-bromobenzenesulfonamide (2.5 g, 10 mmol), and the resultingmixture was stirred at the reflux temp. overnight, cooled to room temp.,and separated between EtOAc (50 mL) and a 1 N HCl solution (50 mL). Theaqueous layer was back-extracted with EtOAc (2×50 mL). The combinedorganic phases were sequentially washed with water (2×50 mL) and asaturated NaCl solution (50 mL), dried (MgSO₄), and concentrated underreduced pressure. The residual oil was purified by column chromatography(30% EtOAc/70% hexane) to give 4-(3-(N-methylsulfamoyl)phenyloxy)benzene(0.30 g).

[0153] Step 3. Synthesis of4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene

[0154] To a solution of 4-(3-(N-methylsulfamoyl)phenyloxy)benzene (0.30g, 1.14 mmol) in TFA (6 mL) at −10° C. was added NaNO₂ (0.097 g, 1.14mmol) in portions over 5 min. The resulting solution was stirred at −10°C. for 1 h, then was allowed to warm to room temp., and was concentratedunder reduced pressure. The residue was separated between EtOAc (10 mL)and water (10 mL). The organic phase was sequentially washed with water(10 mL) and a saturated NaCl solution (10 mL), dried (MgSO₄) andconcentrated under reduced pressure to give4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene (0.20 g). Thismaterial carried on to the next step without further purification.

[0155] Step 4. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)aniline

[0156] A slurry of 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene(0.30 g) and 10% Pd/C (0.030 g) in EtOAc (20 mL) was stirred under an H₂atmosphere (balloon) overnight. The resulting mixture was filteredthrough a pad of Celite®. The filtrate was concentrated under reducedpressure. The residue was purified by column chromatography (30%EtOAc/70% hexane) to give 4-(3-(N-methylsulfamoyl)phenyloxy)aniline(0.070 g).

A16. Modification of ω-ketones. Synthesis of4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl Salt

[0157]

[0158] To a slurry of 4-(4-acetylphenoxy)aniline HCl salt (prepared in amanner analogous to Method A13, step 4; 1.0 g, 3.89 mmol) in a mixtureof EtOH (10 mL) and pyridine (1.0 mL) was added O-methylhydroxylamineHCl salt (0.65 g, 7.78 mmol, 2.0 equiv.). The resulting solution washeated at the reflux temperature for 30 min, cooled to room temperatureand concentrated under reduced pressure. The resulting solids weretriturated with water (10 mL) and washed with water to give4-(4-(1-(N-methoxy)iminoethyl) phenoxyaniline HCl salt as a yellow solid(0.85 g): TLC (50% EtOAc/50% pet. ether) R_(f) 0.78; ¹H NMR (DMSO-d₆)δ3.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m/z 257 ((M+H)⁺).

A17. Synthesis of N-(ω-Silyloxyalkyl)amides. Synthesis of4-(4-(2-(N-(2-Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline

[0159]

[0160] Step 1.4-Chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide

[0161] To a solution of4-chloro-N-(2-hydroxyethyl)pyridine-2-carboxamide (prepared in a manneranalogous to Method A2, Step 3b; 1.5 g, 7.4 mmol) in anh DMF (7 mL) wasadded triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) andimidazole (1.12 g, 16.4 mmol, 2.2 equiv.). The resulting yellow solutionwas stirred for 3 h at room temp, then was concentrated under reducedpressure. The residue was separated between water (10 mL) and EtOAc (10mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combinedorganic phases were dried (MgSO₄), and concentrated under reducedpressure to afford4-chloro-2-(N-(2-triisopropylsilyloxy)ethyl)pyridinecarboxamide as anorange oil (2.32 g, 88%). This material was used in the next stepwithout further purification.

[0162] Step 2.4-(4-(2-(N-(2-Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline

[0163] To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anh DMF(8 mL) was added potassium tert-butoxide (0.67 g, 6.0 mmol, 1.0 equiv.)in one portion causing an exotherm. When this mixture had cooled to roomtemperature, a solution of4-chloro-2-(N-(2-triisopropylsilyloxy)ethyl)pyridinecarboxamide (2.32 g,6 mmol, 1 equiv.) in DMF (4 mL) was added followed by K₂CO₃ (0.42 g, 3.0mmol, 0.50 equiv.). The resulting mixture was heated at 80° C.overnight. An additional portion of potassium tert-butoxide (0.34 g, 3mmol, 0.5 equiv.) was then added and the mixture was stirred at 80° C.an additional 4 h. The mixture was cooled to 0° C. with an ice/waterbath, then water (approx. 1 mL) was slowly added dropwise. The organiclayer was extracted with EtOAc (3×10 mL). The combined organic layerswere washed with a saturated NaCl solution (20 mL), dried (MgSO₄) andconcentrated under reduced pressure. The brown oily residue was purifiedby column chromatography (SiO₂; 30% EtOAc/70% pet ether) to afford4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline as aclear light brown oil (0.99 g, 38%).

A18. Synthesis of 2-Pryidinecarboxylate Esters via Oxidation of2-Methylpyridines. Synthesis of4-(5-(2-methoxycarbonyl)pyridyloxy)aniline

[0164]

[0165] Step 1. 4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene.

[0166] A mixture of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol),1-fluoro-4-nitrobenzene (9.8 mL, 91.6 mmol, 1.0 equiv.), K₂CO₃ (25 g,183 mmol, 2.0 equiv.) in DMF (100 mL) was heated at the refluxtemperature overnight. The resulting mixture was cooled to roomtemperature, treated with water (200 mL), and extracted with EtOAc(3×100 mL). The combined organic layers were sequentially washed withwater (2×100 mL) and a saturated NaCl solution ((100 mL), dried (MgSO₄)and concentrated under reduced pressure to give4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene as a brown solid (12.3 g).

[0167] Step 2. Synthesis of4-(5-(2-Methoxycarbonyl)pyridyloxy)-1-nitrobenzene.

[0168] A mixture of 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene (1.70 g,7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3.0 equiv.) inpyridine (20 mL) was heated at the reflux temperature for 5 h, thencooled to room temperature. The resulting slurry was filtered, thenconcentrated under reduced pressure. The residue was dissolved in MeOH(100 mL). The solution was treated with a conc HCl solution (7 mL), thenheated at the reflux temperature for 3 h, cooled to room temperature andconcentrated under reduced pressure. The residue was separated betweenEtOAc (50 mL) and a 1N NaOH solution (50 mL). The aqueous layer wasextracted with EtOAc (2×50 mL). The combined organic layers weresequentially washed with water (2×50 mL) and a saturated NaCl solution(50 mL), dried (MgSO₄) and concentrated under reduced pressure. Theresidue was purified by column chromatography (SiO₂; 50% EtOAc/50%hexane) to afford 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene(0.70 g).

[0169] Step 3. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)aniline.

[0170] A slurry of 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene(0.50 g) and 10% Pd/C (0.050 g) in a mixture of EtOAc (20 mL) and MeOH(5 mL) was placed under a H₂ atmosphere (balloon) overnight. Theresulting mixture was filtered through a pad of Celite®, and thefiltrate was concentrated under reduced pressure. The residue waspurified by column chromatography (SiO₂; 70% EtOAc/30% hexane) to give4-(5-(2-methoxycarbonyl)pyridyloxy)aniline (0.40 g).

A19. Synthesis of ω-Sulfonylphenyl Anilines. Synthesis of4-(4-Methylsulfonylphenyoxy)aniline

[0171]

[0172] Step 1. 4-(4-Methylsulfonylphenoxy)-1-nitrobenzene: To a solutionof 4-(4-methylthiophenoxy)-1-nitrobenzene (2.0 g, 7.7 mmol) in CH₂Cl₂(75 mL) at 0° C. was slowly added m-CPBA (57-86%, 4.0 g), and thereaction mixture was stirred at room temperature for 5 h. The reactionmixture was treated with a 1N NaOH solution (25 mL). The organic layerwas sequentially washed with a 1N NaOH solution (25 mL), water (25 mL)and a saturated NaCl solution (25 mL), dried (MgSO₄), and concentratedunder reduced pressure to give4-(4-methylsulfonylphenoxy)-1-nitrobenzene as a solid (2.1 g).

[0173] Step 2. 4-(4-Methylsulfonylphenoxy)-1-aniline:4-(4-Methylsulfonylphenoxy)-1-nitrobenzene was reduced to the aniline ina manner analogous to that described in Method A18, step 3.

[0174] B. Synthesis of Urea Precursors

B1. General Method for the Synthesis of Isocyanates from Anilines UsingCDI. Synthesis of 4-Bromo-3-(trifluoromethyl)phenyl Isocyanate

[0175]

[0176] Step 1. Synthesis of 4-bromo-3-(trifluoromethyl)aniline HCl salt

[0177] To a solution of 4-bromo-3-(trifluoromethyl)aniline (64 g, 267mmol) in Et₂O (500 mL) was added an HCl solution (1 M in Et₂O; 300 mL)dropwise and the resulting mixture was stirred at room temp. for 16 h.The resulting pink-white precipitate was removed by filtration andwashed with Et₂O (50 mL) and to afford4-bromo-3-(trifluoromethyl)aniline HCl salt (73 g, 98%).

[0178] Step 2. Synthesis of 4-bromo-3-(trifluoromethyl)phenyl Isocyanate

[0179] A suspension of 4-bromo-3-(trifluoromethyl)aniline HCl salt (36.8g, 133 mmol) in toluene (278 mL) was treated with trichloromethylchloroformate dropwise and the resulting mixture was heated at thereflux temp. for 18 h. The resulting mixture was concentrated underreduced pressure. The residue was treated with toluene (500 mL), thenconcentrated under reduced pressure. The residue was treated with CH₂Cl₂(500 mL), then concentrated under reduced pressure. The CH₂Cl₂treatment/concentration protocol was repeated and resulting amber oilwas stored at −20° C. for 16 h, to afford4-bromo-3-(trifluoromethyl)phenyl isocyanate as a tan solid (35.1 g,86%): GC-MS m/z 265 (M⁺).

[0180] C. Methods of Urea Formation

C1a. General Method for the Synthesis of Ureas by Reaction of anIsocyanate with an Aniline. Synthesis ofN-(4-Chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)Urea

[0181]

[0182] A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate(14.60 g, 65.90 mmol) in CH₂Cl₂ (35 mL) was added dropwise to asuspension of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (Method A2,Step 4; 16.0 g, 65.77 mmol) in CH₂Cl₂ (35 mL) at 0° C. The resultingmixture was stirred at room temp. for 22 h. The resulting yellow solidswere removed by filtration, then washed with CH₂Cl₂ (2×30 mL) and driedunder reduced pressure (approximately 1 mmHg) to affordN-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea as an off-white solid (28.5 g, 93%): mp 207-209° C.; ¹H-NMR(DMSO-d₆) δ2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5 Hz, 1H),7.62 (m, 4H), 8.11 (d, J=2.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.77 (brd, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 465 ((M+H)⁺).

C1b. General Method for the Synthesis of Ureas by Reaction of anIsocyanate with an Aniline. Synthesis ofN-(4-Bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)Urea

[0183]

[0184] A solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate(Method B1, Step 2; 8.0 g, 30.1 mmol) in CH₂Cl₂ (80 mL) was addeddropwise to a solution of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline(Method A2, Step 4; 7.0 g, 28.8 mmol) in CH₂Cl₂ (40 mL) at 0° C. Theresulting mixture was stirred at room temp. for 16 h. The resultingyellow solids were removed by filtration, then washed with CH₂Cl₂ (2×50mL) and dried under reduced pressure (approximately 1 mmHg) at 40° C. toaffordN-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea as a pale-yellow solid (13.2 g, 90%): mp 203-205° C.; ¹H-NMR(DMSO-d₆) δ2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5 Hz, 1H),7.58 (m, 3H), 7.77 (d, J=8.8 Hz, 1H), 8.11 (d, J=2.5 Hz, 1H), 8.49 (d,J=5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MSm/z 509 ((M+H)⁺).

C1c. General Method for the Synthesis of Ureas by Reaction of anIsocyanate with an Aniline. Synthesis ofN-(4-Chloro-3-(trifluoromethyl)phenyl)-N′-(2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)Urea

[0185]

[0186] A solution of2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))aniline (Method A5; 0.11g, 0.45 mmol) in CH₂Cl₂ (1 mL) was treated with Et₃N (0.16 mL) and4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). Theresulting brown solution was stirred at room temp. for 6 d, then wastreated with water (5 mL). The aqueous layer was back-extracted withEtOAc (3×5 mL). The combined organic layers were dried (MgSO₄) andconcentrated under reduced pressure to yieldN-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea as a brown oil (0.11 g, 0.22 mmol): ¹H NMR (DMSO-d₆) δ2.27 (s, 3H),2.77 (d, J=4.8 Hz, 3H), 7.03 (dd, J=8.5, 2.6 Hz, 1H), 7.11 (d, J=2.9 Hz,1H), 7.15 (dd, J=5.5, 2.6, Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.62 (app d,J=2.6 Hz, 2H), 7.84 (d, J=8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H); 8.50(d, J=5.5 Hz, 1H), 8.78 (q, J=5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m/z 479((M+H)⁺).

C1d. General Method for the Synthesis of Ureas by Reaction of anIsocyanate with an Aniline. Synthesis ofN-(4-Chloro-3-(trifluoromethyl)phenyl)-N′-(4-aminophenyl) Urea

[0187]

[0188] To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate(2.27 g, 10.3 mmol) in CH₂Cl₂ (308 mL) was added p-phenylenediamine(3.32 g, 30.7 mmol) in one part. The resulting mixture was stirred atroom temp. for 1 h, treated with CH₂Cl₂ (100 mL), and concentrated underreduced pressure. The resulting pink solids were dissolved in a mixtureof EtOAc (110 mL) and MeOH (15 mL), and the clear solution was washedwith a 0.05 N HCl solution. The organic layer was concentrated underreduced pressure to afford impureN-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-aminophenyl) urea (3.3 g):TLC (100% EtOAc) R_(f) 0.72.

C1e. General Method for the Synthesis of Ureas by Reaction of anIsocyanate with an Aniline. Synthesis ofN-(4-Chloro-3-(trifluoromethyl)phenyl)-N′-(4-ethoxycarbonylphenyl) Urea

[0189]

[0190] To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol)in CH₂Cl₂ (30 mL) was added 4-chloro-3-(trifluoromethyl)aniline (3.21 g,16.4 mmol), and the solution was stirred at room temp. overnight. Theresulting slurry was diluted with CH₂Cl₂ (50 mL) and filtered to affordN-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-ethoxycarbonylphenyl) ureaas a white solid (5.93 g, 97%): TLC (40% EtOAc/60% hexane) R_(f) 0.44.

C1f. General Method for the Synthesis of Ureas by Reaction of anIsocyanate with an Aniline. Synthesis ofN-(4-Chloro-3-(trifluoromethyl)phenyl)-N′-(3-carboxyphenyl) Urea

[0191]

[0192] To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate(1.21 g, 5.46 mmol) in CH₂Cl₂ (8 mL) was added4-(3-carboxyphenoxy)aniline (Method A11; 0.81 g, 5.76 mmol) and theresulting mixture was stirred at room temp. overnight, then treated withMeOH (8 mL), and stirred an additional 2 h. The resulting mixture wasconcentrated under reduced pressure. The resulting brown solids weretriturated with a 1:1 EtOAc/hexane solution to giveN-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(3-carboxyphenyl) urea as anoff-white solid (1.21 g, 76%).

C2a. General Method for Urea Synthesis by Reaction of an Aniline withN,N′-Carbonyl Diimidazole Followed by Addition of a Second Aniline.Synthesis ofN-(2-Methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)Urea

[0193]

[0194] To a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) inanh CH₂Cl₂ (15 mL) at 0° C. was added CDI (0.13 g). The resultingsolution was allowed to warm to room temp. over 1 h, was stirred at roomtemp. for 16 h, then was treated with4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g). The resultingyellow solution was stirred at room temp. for 72 h, then was treatedwith H₂O (125 mL). The resulting aqueous mixture was extracted withEtOAc (2×150 mL). The combined organics were washed with a saturatedNaCl solution (100 mL), dried (MgSO₄) and concentrated under reducedpressure. The residue was triturated (90% EtOAc/10% hexane). Theresulting white solids were collected by filtration and washed withEtOAc. The filtrate was concentrated under reduced pressure and theresidual oil purified by column chromatography (gradient from 33%EtOAc/67% hexane to 50% EtOAc/50% hexane to 100% EtOAc) to giveN-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea as a light tan solid (0.098 g, 30%): TLC (100% EtOAc) R_(f) 0.62;¹H NMR (DMSO-d₆) δ2.76 (d, J=4.8 Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and8.4-8.6 (m, 11H), 8.75 (d, J=4.8 Hz, 1H), 9.55 (s, 1H); FAB-MS m/z 461((M+H)⁺).

C2b. General Method for Urea Synthesis by Reaction of an Aniline withN,N′-Carbonyl Diimidazole Followed by Addition of a Second Aniline.Symmetrical Urea's as Side Products of a N,N′-Carbonyl DiimidazoleReaction Procedure. Synthesis ofBis(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) Urea

[0195]

[0196] To a stirring solution of 3-amino-2-methoxyquinoline (0.14 g) inanhydrous CH₂Cl₂ (15 mL) at 0° C. was added CDI (0.13 g). The resultingsolution was allowed to warm to room temp. over 1 h then was stirred atroom temp. for 16 h. The resulting mixture was treated with4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g). The resultingyellow solution stirred at room temp. for 72 h, then was treated withwater (125 mL). The resulting aqueous mixture was extracted with EtOAc(2×150 mL). The combined organic phases were washed with a saturatedNaCl solution (100 ml), dried (MgSO₄) and concentrated under reducedpressure. The residue was triturated (90% EtOAc/10% hexane). Theresulting white solids were collected by filtration and washed withEtOAc to give bis(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea(0.081 g, 44%): TLC (100% EtOAc) R_(f) 0.50; ¹H NMR (DMSO-d₆) δ2.76 (d,J=5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J=5.4 Hz, 1H), 8.75 (d, J=4.8Hz, 2H), 8.86 (s, 2H); HPLC ES-MS m/z 513 ((M+H)⁺).

C2c. General Method for the Synthesis of Ureas by Reaction of anIsocyanate with an Aniline. Synthesis ofN-(2-Methoxy-5-(trifluoromethyl)phenyl-N′-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl)Urea

[0197]

[0198] To a stirring solution of 2-methoxy-5-(trifluoromethyl)phenylisocyanate (0.10 g, 0.47 mmol) in CH₂Cl₂ (1.5 mL) was added5-(4-aminophenoxy)isoindoline-1,3-dione (Method A3, Step 3; 0.12 g, 0.47mmol) in one portion. The resulting mixture was stirred for 12 h, thenwas treated with CH₂Cl₂ (10 mL) and MeOH (5 mL). The resulting mixturewas sequentially washed with a 1N HCl solution (15 mL) and a saturatedNaCl solution (15 mL), dried (MgSO₄) and concentrated under reducedpressure to affordN-(2-methoxy-5-(trifluoromethyl)phenyl-N′-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl)urea as a white solid (0.2 g, 96%): TLC (70% EtOAc/30% hexane) R_(f)0.50; ¹H NMR (DMSO-d₆) δ3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J=9.3Hz, 2H), 7.80 (d, J=8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H), 11.27(br s, 1H); HPLC ES-MS 472.0 ((M+H)⁺, 100%).

C2d. General Method for Urea Synthesis by Reaction of an Aniline withN,N′-Carbonyl Diimidazole Followed by Addition of a Second Aniline.Synthesis ofN-(5-(tert-Butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)Urea

[0199]

[0200] To a stirring solution of CDI (0.21 g, 1.30 mmol) in CH₂Cl₂ (2mL) was added 5-(tert-butyl)-2-(2,5-dimethylpyrrolyl)aniline (Method A4,Step 2; 0.30 g, 1.24 mmol) in one portion. The resulting mixture wasstirred at room temp. for 4 h, then4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.065 g, 0.267 mmol) wasthen added in one portion. The resulting mixture was heated at 36° C.overnight, then cooled to room temp. and diluted with EtOAc (5 mL). Theresulting mixture was sequentially washed with water (15 mL) and a 1NHCl solution (15 mL), dried (MgSO₄), and filtered through a pad ofsilica gel (50 g) to affordN-(5-(tert-butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc/60% hexane)R_(f) 0.24; ¹H NMR (acetone-d₆) δ1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d,J=4.8 Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58(m, 3H), 8.43 (d, J=5.4 Hz, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.80 (br s,1H); HPLC ES-MS 512 ((M+H)⁺, 100%).

C3. Combinatorial Method for the Synthesis of Diphenyl Ureas UsingTriphosgene

[0201] One of the anilines to be coupled was dissolved in dichloroethane(0.10 M). This solution was added to a 8 mL vial (0.5 mL) containingdichloroethane (1 mL). To this was added a bis(trichloromethyl)carbonate solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv.),followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2equiv.). The vial was capped and heat at 80° C. for 5 h, then allowed tocool to room temp for approximately 10 h. The second aniline was added(0.10 M in dichloroethane, 0.5 mL, 1.0 equiv.), followed bydiisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.).The resulting mixture was heated at 80° C. for 4 h, cooled to roomtemperature and treated with MeOH (0.5 mL). The resulting mixture wasconcentrated under reduced pressure and the products were purified byreverse phase HPLC.

C4. General Method for Urea Synthesis by Reaction of an Aniline withPhosgene Followed by Addition of a Second Aniline. Synthesis ofN-(2-Methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)Urea

[0202]

[0203] To a stirring solution of phosgene (1.9 M in toluene; 2.07 mL0.21g, 1.30 mmol) in CH₂Cl₂ (20 mL) at 0° C. was added anh pyridine (0.32mL) followed by 2-methoxy-5-(trifluoromethyl)aniline (0.75 g). Theyellow solution was allowed to warm to room temp during which aprecipitate formed. The yellow mixture was stirred for 1 h, thenconcentrated under reduced pressure. The resulting solids were treatedwith anh toluene (20 mL) followed by4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (prepared as described inMethod A2; 0.30 g) and the resulting suspension was heated at 80° C. for20 h, then allowed to cool to room temp. The resulting mixture wasdiluted with water (100 mL), then was made basic with a saturated NaHCO₃solution (2-3 mL). The basic solution was extracted with EtOAc (2×250mL). The organic layers were separately washed with a saturated NaClsolution, combined, dried (MgSO₄), and concentrated under reducedpressure. The resulting pink-brown residue was dissolved in MeOH andabsorbed onto SiO₂ (100 g). Column chromatography (300 g SiO₂; gradientfrom 1% Et₃N/33% EtOAc/66% hexane to 1% Et₃N/99% EtOAc to 1% Et₃N/20%MeOH/79% EtOAc) followed by concentration under reduced pressure at 45°C. gave a warm concentrated EtOAc solution, which was treated withhexane (10 mL) to slowly form crystals ofN-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea (0.44 g): TLC (1% Et₃N/99% EtOAc) R_(f) 0.40.

[0204] D. Interconversion of Ureas

D1a. Conversion of ω-Aminophenyl Ureas into ω-(Aroylamino)phenyl Ureas.Synthesis ofN-(4-Chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl)Urea

[0205]

[0206] To a solution ofN-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-aminophenyl) urea (MethodC1d; 0.050 g, 1.52 mmol), mono-methyl isophthalate (0.25 g, 1.38 mmol),HOBT.H₂O (0.41 g, 3.03 mmol) and N-methylmorpholine (0.33 mL, 3.03 mmol)in DMF (8 mL) was added EDCI.HCl (0.29 g, 1.52 mmol). The resultingmixture was stirred at room temp. overnight, diluted with EtOAc (25 mL)and sequentially washed with water (25 mL) and a saturated NaHCO₃solution (25 mL). The organic layer was dried (Na₂SO₄) and concentratedunder reduced pressure. The resulting solids were triturated with anEtOAc solution (80% EtOAc/20% hexane) to giveN-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl)urea (0.27 g, 43%): mp 121-122; TLC (80% EtOAc/20% hexane) R_(f) 0.75.

D1b. Conversion of ω-Carboxyphenyl Ureas into ω-(Arylcarbamoyl)phenylUreas. Synthesis ofN-(4-Chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-methylcarbamoylphenyl)carbamoylphenyl)Urea

[0207]

[0208] To a solution ofN-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl)urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53 mmol),HOBT.H₂O (0.14 g, 1.07 mmol), and N-methylmorpholine (0.5 mL, 1.07 mmol)in DMF (3 mL) at 0° C. was added EDCI.HCl (0.10 g, 0.53 mmol). Theresulting mixture was allowed to warm to room temp. and was stirredovernight. The resulting mixture was treated with water (10 mL), andextracted with EtOAc (25 mL). The organic phase was concentrated underreduced pressure. The resulting yellow solids were dissolved in EtOAc (3mL) then filtered through a pad of silica gel (17 g, gradient from 70%EtOAc/30% hexane to 10% MeOH/90% EtOAc) to giveN-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-methylcarbamoylphenyl)carbamoylphenyl)urea as a white solid (0.097 g, 41%): mp 225-229; TLC (100% EtOAc) R_(f)0.23.

D1c. Combinatorial Approach to the Conversion of ω-Carboxyphenyl Ureasinto ω-(Arylcarbamoyl)phenyl Ureas. Synthesis ofN-(4-Chloro-3-((trifluoromethyl)phenyl)-N′-(4-(N-(3-(N-(3-pyridyl)carbamoyl)phenyl)carbamoyl)phenyl)Urea

[0209]

[0210] A mixture ofN-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(3-carboxyphenyl) urea(Method C1f; 0.030 g, 0.067 mmol) andN-cyclohexyl-N′-(methylpolystyrene)carbodiimide (55 mg) in1,2-dichloroethane (1 mL) was treated with a solution of 3-aminopyridinein CH₂Cl₂ (1 M; 0.074 mL, 0.074 mmol). (In cases of insolubility orturbidity, a small amount of DMSO was also added.) The resulting mixturewas heated at 36° C. overnight. Turbid reactions were then treated withTHF (1 mL) and heating was continued for 18 h. The resulting mixtureswere treated with poly(4-(isocyanatomethyl)styrene) (0.040 g) and theresulting mixture was stirred at 36° C. for 72 h, then cooled to roomtemp. and filtered. The resulting solution was filtered through a plugof silica gel (1 g). Concentration under reduced pressure affordedN-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(N-(3-(N-(3-pyridyl)carbamoyl)phenyl)carbamoyl)phenyl)urea (0.024 g, 59%): TLC (70% EtOAc/30% hexane) R_(f) 0.12.

D2. Conversion of ω-Carboalkoxyaryl Ureas into ω-Carbamoylaryl Ureas.Synthesis ofN-(4-Chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl)Urea

[0211]

[0212] To a sample ofN-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-carbomethoxyphenyl)carboxyaminophenyl)urea (0.17 g, 0.34 mmol) was added methylamine (2 M in THF; 1 mL, 1.7mmol) and the resulting mixture was stirred at room temp. overnight,then concentrated under reduced pressure to giveN-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl)urea as a white solid: mp 247; TLC (100% EtOAc) R_(f) 0.35.

D3. Conversion of ω-Carboalkoxyaryl Ureas into ω-Carboxyaryl Ureas.Synthesis ofN-(4-Chloro-3-((trifluoromethyl)phenyl)-N′-(4-carboxyphenyl) Urea

[0213]

[0214] To a slurry ofN-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-ethoxycarbonylphenyl) urea(Method C1e; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added an aqueous KOHsolution (2.5 N, 10 mL, 23 mmol). The resulting mixture was heated atthe reflux temp. for 12 h, cooled to room temp., and concentrated underreduced pressure. The residue was diluted with water (50 mL), thentreated with a 1 N HCl solution to adjust the pH to 2 to 3. Theresulting solids were collected and dried under reduced pressure to giveN-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-carboxyphenyl) urea as awhite solid (5.05 g, 92%).

D4. General Method for the Conversion of ω-Alkoxy Esters into ω-AlkylAmides. Synthesis ofN-(4-Chloro-3-((trifluoromethyl)phenyl)-N′-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl)Urea

[0215]

[0216] Step 1. Synthesis ofN-(4-Chloro-3-(trifluoromethyl)phenyl)-N′-((4-(3-(5-carboxypyridyl)oxyphenyl)Urea

[0217]N-(4-Chloro-3-(trifluoromethyl)phenyl)-N′-((4-(3-(5-methoxycarbonylpyridyl)oxyphenyl)urea was synthesized from 4-chloro-3-(trifluoromethyl)phenyl isocyanateand 4-(3-(5-methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2) in amanner analogous to Method C1a. A suspension ofN-(4-chloro-3-(trifluoromethyl)phenyl)-N′-((4-(3-(5-methoxycarbonylpyridyl)oxyphenyl)urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with a solution ofKOH (0.14 g, 2.5 mmol) in water (1 mL) and was stirred at room temp. for1 h. The resulting mixture was adjusted to pH 5 with a 1 N HCl solution.The resulting precipitate was removed by filtration and washed withwater. The resulting solids were dissolved in EtOH (10 mL) and theresulting solution was concentrated under reduced pressure. TheEtOH/concentration procedure was repeated twice to giveN-(4-chloro-3-(trifluoromethyl)phenyl)-N′-((4-(3-(5-carboxypyridyl)oxyphenyl)urea (0.18 g, 71%).

[0218] Step 2. Synthesis ofN-(4-chloro-3-(trifluoromethyl)phenyl)-N′-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl)urea

[0219] A mixture ofN-(4-chloro-3-(trifluoromethyl)phenyl)-N′-((4-(3-(5-carboxypyridyl)oxyphenyl)urea (0.050 g, 0.011 mmol), N,N-dimethylethylenediamine (0.22 mg, 0.17mmol), HOBT (0.028 g, 0.17 mmol), N-methylmorpholine (0.035 g, 0.28mmol), and EDCI.HCl (0.032 g, 0.17 mmol) in DMF (2.5 mL) was stirred atroom temp. overnight. The resulting solution was separated between EtOAc(50 mL) and water (50 mL). The organic phase was washed with water (35mL), dried (MgSO₄) and concentrated under reduced pressure. The residuewas dissolved in a minimal amount of CH₂Cl₂ (approximately 2 mL). Theresulting solution was treated with Et₂O dropwise to giveN-(4-chloro-3-(trifluoromethyl)phenyl)-N′-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl)urea as a white precipitate (0.48 g, 84%: ¹H NMR (DMSO-d₆) δ2.10 s, 6H),3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), 8.05 (s, 1H),8.43 (s, 1H), 8.58 (t, 1H), 8.69 (s, 1H), 8.90 (s, 1H), 9.14 (s, 1H);HPLC ES-MS m/z 522 ((M+H)⁺).

D5. General Method for the Deprotection of N-(ω-Silyloxyalkyl)amides.Synthesis ofN-(4-Chloro-3-((trifluoromethyl)phenyl)-N′-(4-(4-(2-(N-(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl)Urea

[0220]

[0221] To a solution ofN-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyphenyl)urea (prepared in a manner analogous to Method C1a; 0.25 g, 0.37 mmol)in anh THF (2 mL) was tetrabutylammonium fluoride (1.0 M in THF; 2 mL).The mixture was stirred at room temperature for 5 min, then was treatedwith water (10 mL). The aqueous mixture was extracted with EtOAc (3×10mL). The combined organic layers were dried (MgSO₄) and concentratedunder reduced pressure. The residue was purified by columnchromatography (SiO₂; gradient from 100% hexane to 40% EtOAc/60% hexane)to giveN-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(4-(2-(N-(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl)urea as a white solid (0.019 g, 10%).

[0222] Listed below are compounds listed in the Tables below which havebeen synthesized according to the Detailed Experimental Procedures givenabove:

Syntheses of Exemplified Compounds (see Tables for CompoundCharacterization)

[0223] Entry 1: 4-(3-N-Methylcarbamoylphenoxy)aniline was preparedaccording to Method A13. According to Method C3, 3-tert-butylaniline wasreacted with bis(trichloromethyl)carbonate followed by4-(3-N-Methylcarbamoylphenoxy)aniline to afford the urea.

[0224] Entry 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone werereacted according to Method A13, Step 1 to afford the4-(4-acetylphenoxy)-1-nitrobenzene. 4-(4-Acetylphenoxy)-1-nitrobenzenewas reduced according to Method A13, Step 4 to afford4-(4-acetylphenoxy)aniline. According to Method C3, 3-tert-butylanilinewas reacted with bis(trichloromethyl) carbonate followed by4-(4-acetylphenoxy)aniline to afford the urea.

[0225] Entry 3: According to Method C2d, 3-tert-butylaniline was treatedwith CDI, followed by 4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline,which had been prepared according to Method A8, to afford the urea.

[0226] Entry 4: 5-tert-Butyl-2-methoxyaniline was converted to5-tert-butyl-2-methoxyphenyl isocyanate according to Method B1.4-(3-N-Methylcarbamoylphenoxy)aniline, prepared according to Method A13,was reacted with the isocyanate according to Method C1a to afford theurea.

[0227] Entry 5: According to Method C2d, 5-tert-butyl-2-methoxyanilinewas reacted with CDI followed by4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had beenprepared according to Method A8, to afford the urea.

[0228] Entry 6: 5-(4-Aminophenoxy)isoindoline-1,3-dione was preparedaccording to Method A3. According to Method 2d,5-tert-butyl-2-methoxyaniline was reacted with CDI followed by5-(4-aminophenoxy)isoindoline-1,3-dione to afford the urea.

[0229] Entry 7: 4-(1-Oxoisoindolin-5-yloxy)aniline was synthesizedaccording to Method A12. According to Method 2d,5-tert-butyl-2-methoxyaniline was reacted with CDI followed by4-(1-oxoisoindolin-5-yloxy)aniline to afford the urea.

[0230] Entry 8: 4-(3-N-Methylcarbamoylphenoxy)aniline was synthesizedaccording to Method A13. According to Method C2a,2-methoxy-5-(trifluoromethyl)aniline was reacted with CDI followed by4-(3-N-methylcarbamoylphenoxy)aniline to afford the urea.

[0231] Entry 9: 4-Hydroxyacetophenone was reacted with2-chloro-5-nitropyridine to give 4-(4-acetylphenoxy)-5-nitropyridineaccording to Method A3, Step 2. According to Method A8, Step 4,4-(4-acetylphenoxy)-5-nitropyridine was reduced to4-(4-acetylphenoxy)-5-aminopyridine.2-Methoxy-5-(trifluoromethyl)aniline was converted to2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1.The isocyanate was reacted with 4-(4-acetylphenoxy)-5-aminopyridineaccording to Method C1a to afford the urea.

[0232] Entry 10: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone werereacted according to Method A13, Step 1 to afford the4-(4-acetylphenoxy)-1-nitrobenzene. 4-(4-Acetylphenoxy)-1-nitrobenzenewas reduced according to Method A13, Step 4 to afford4-(4-acetylphenoxy)aniline. According to Method C3,5-(trifluoromethyl)-2-methoxybutylaniline was reacted withbis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline toafford the urea.

[0233] Entry 11: 4-Chloro-N-methyl-2-pyridinecarboxamide, which wassynthesized according to Method A2, Step 3a, was reacted with3-aminophenol according to Method A2, Step 4 using DMAC in place of DMFto give 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According toMethod C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted withphosgene followed by 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline toafford the urea.

[0234] Entry 12: 4-Chloropyridine-2-carbonyl chloride HCl salt wasreacted with ammonia according to Method A2, Step 3b to form4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide wasreacted with 3-aminophenol according to Method A2, Step 4 using DMAC inplace of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline. According toMethod C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted withphosgene followed by 3-(2-carbamoyl-4-pyridyloxy)aniline to afford theurea.

[0235] Entry 13: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesizedaccording to Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamidewas reacted with 4-aminophenol according to Method A2, Step 4 using DMACin place of DMF to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline.According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline wasreacted with CDI followed by4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

[0236] Entry 14: 4-Chloropyridine-2-carbonyl chloride HCl salt wasreacted with ammonia according to Method A2, Step 3b to form4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide wasreacted with 4-aminophenol according to Method A2, Step 4 using DMAC inplace of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline. According toMethod C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted withphosgene followed by 4-(2-carbamoyl-4-pyridyloxy)aniline to afford theurea.

[0237] Entry 15: According to Method C2d,5-(triflouromethyl)-2-methoxyaniline was reacted with CDI followed by4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had beenprepared according to Method A8, to afford the urea.

[0238] Entry 16: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylanilinewas synthesized according to Method A5.5-(Trifluoromethyl)-2-methoxyaniline was converted into5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.The isocyanate was reacted with4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-methylaniline according toMethod C1c to afford the urea.

[0239] Entry 17: 4-(2-(N-Methytcarbamoyl)-4-pyridyloxy)-2-chloroanilinewas synthesized according to Method A6.5-(Trifluoromethyl)-2-methoxyaniline was converted into5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline according toMethod C1a to afford the urea.

[0240] Entry 18: According to Method A2, Step 4, 5-amino-2-methylphenolwas reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had beensynthesized according to Method A2, Step 3b, to give3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline.5-(Trifluoromethyl)-2-methoxyaniline was converted into5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline according toMethod C1a to afford the urea.

[0241] Entry 19: 4-Chloropyridine-2-carbonyl chloride was reacted withethylamine according to Method A2, Step 3b. The resulting4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenolaccording to Method A2, Step 4 to give4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline.5-(Trifluoromethyl)-2-methoxyaniline was converted into5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline according to Method C1a toafford the urea.

[0242] Entry 20: According to Method A2, Step 4, 4-amino-2-chlorophenolwas reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had beensynthesized according to Method A2, Step 3b, to give4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline.5-(Trifluoromethyl)-2-methoxyaniline was converted into5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline according toMethod C1a to afford the urea.

[0243] Entry 21: 4-(4-Methylthiophenoxy)-1-nitrobenzene was oxidizedaccording to Method A19, Step 1 to give4-(4-methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene was reducedaccording to Method A19, Step 2 to give4-(4-methylsulfonylphenoxy)-1-aniline. According to Method C1a,5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with4-(4-methylsulfonylphenoxy)-1-aniline to afford the urea.

[0244] Entry 22: 4-(3-carbamoylphenoxy)-1-nitrobenzene was reduced to4-(3-carbamoylphenoxy)aniline according to Method A15, Step 4. Accordingto Method C1a, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate wasreacted with 4-(3-carbamoylphenoxy)aniline to afford the urea.

[0245] Entry 23: 5-(4-Aminophenoxy)isoindoline-1,3-dione was synthesizedaccording to Method A3. 5-(Trifluoromethyl)-2-methoxyaniline wasconverted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate accordingto Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reactedwith 5-(4-aminophenoxy)isoindoline-1,3-dione according to Method C1a toafford the urea.

[0246] Entry 24: 4-Chloropyridine-2-carbonyl chloride was reacted withdimethylamine according to Method A2, Step 3b. The resulting4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with4-aminophenol according to Method A2, Step 4 to give4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline.5-(Trifluoromethyl)-2-methoxyaniline was converted into5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline according to MethodC1a to afford the urea.

[0247] Entry 25: 4-(1-Oxoisoindolin-5-yloxy)aniline was synthesizedaccording to Method A12. 5-(Trifluoromethyl)-2-methoxyaniline wastreated with CDI, followed by 4-(1-oxoisoindolin-5-yloxy)anilineaccording to Method C2d to afford the urea.

[0248] Entry 26: 4-Hydroxyacetophenone was reacted with4-fluoronitrobenzene according to Method A13, Step 1 to give4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced accordingto Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which wasconverted to the 4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl saltaccording to Method A16. 5-(Trifluoromethyl)-2-methoxyaniline wasconverted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate accordingto Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reactedwith 4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt to Method C1ato afford the urea.

[0249] Entry 27: 4-Chloro-N-methylpyridinecarboxamide was synthesized asdescribed in Method A2, Step 3b. The chloropyridine was reacted with4-aminothiophenol according to Method A2, Step 4 to give4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline.5-(Trifluoromethyl)-2-methoxyaniline was converted into5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline according to Method C1a toafford the urea.

[0250] Entry 28: 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione wassynthesized according to Method A9. 5-(Trifluoromethyl)-2-methoxyanilinewas converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanateaccording to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanatewas reacted with 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dioneaccording to Method C1a to afford the urea.

[0251] Entry 29: 4-Chloro-N-methylpyridinecarboxamide was synthesized asdescribed in Method A2, Step 3b. The chloropyridine was reacted with3-aminothiophenol according to Method A2, Step 4 to give3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline.5-(Trifluoromethyl)-2-methoxyaniline was converted into5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline according to Method C1a toafford the urea.

[0252] Entry 30: 4-Chloropyridine-2-carbonyl chloride was reacted withisopropylamine according to Method A2, Step 3b. The resulting-4-chloro-N-isopropyl-2-pyridinecarboxamide was reacted with4-aminophenol according to Method A2, Step 4 to give4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline.5-(Trifluoromethyl)-2-methoxyaniline was converted into5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline according to Method C1ato afford the urea.

[0253] Entry 31: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline wassynthesized according to Method A14.5-(Trifluoromethyl)-2-methoxyaniline was converted into5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1a toafford the urea.N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N′-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea was saponified according to Method D4, Step 1, and thecorresponding acid was coupled with 4-(2-aminoethyl)morpholine to affordthe amide according to Method D4, Step 2.

[0254] Entry 32: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline wassynthesized according to Method A14.5-(Trifluoromethyl)-2-methoxyaniline was converted into5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1a toafford the urea.N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N′-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea was saponified according to Method D4, Step 1, and thecorresponding acid was coupled with methylamine according to Method D4,Step 2 to afford the amide.

[0255] Entry 33: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline wassynthesized according to Method A14.5-(Trifluoromethyl)-2-methoxyaniline was converted into5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1a toafford the urea.N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N′-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea was saponified according to Method D4, Step 1, and thecorresponding acid was coupled with N,N-dimethylethylenediamineaccording to Method D4, Step 2 to afford the amide.

[0256] Entry 34: 4-(3-Carboxyphenoxy)aniline was synthesized accordingto Method A11. 5-(Trifluoromethyl)-2-methoxyaniline was converted into5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.4-(3-Carboxyphenoxy)aniline was reacted with5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1fto afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N′-(3-carboxyphenyl)urea, which was coupled with 3-aminopyridine according to Method D1c.

[0257] Entry 35: 4-(3-Carboxyphenoxy)aniline was synthesized accordingto Method A11. 5-(Trifluoromethyl)-2-methoxyaniline was converted into5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.4-(3-Carboxyphenoxy)aniline was reacted with5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1fto afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N′-(3-carboxyphenyl)urea, which was coupled with N-(4-fluorophenyl)piperazine according toMethod D1c.

[0258] Entry 36: 4-(3-Carboxyphenoxy)aniline was synthesized accordingto Method A11. 5-(Trifluoromethyl)-2-methoxyaniline was converted into5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.4-(3-Carboxyphenoxy)aniline was reacted with5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1fto afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N′-(3-carboxyphenyl)urea, which was coupled with 4-fluoroaniline according to Method D1c.

[0259] Entry 37: 4-(3-Carboxyphenoxy)aniline was synthesized accordingto Method A11. 5-(Trifluoromethyl)-2-methoxyaniline was converted into5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.4-(3-Carboxyphenoxy)aniline was reacted with5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1fto afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N′-(3-carboxyphenyl)urea, which was coupled with 4-(dimethylamino)aniline according toMethod D1c.

[0260] Entry 38: 4-(3-Carboxyphenoxy)aniline was synthesized accordingto Method A11. 5-(Trifluoromethyl)-2-methoxyaniline was converted into5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.4-(3-Carboxyphenoxy)aniline was reacted with5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1fto afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N′-(3-carboxyphenyl)urea, which was coupled with 5-amino-2-methoxypyridine according toMethod D1c.

[0261] Entry 39: 4-(3-Carboxyphenoxy)aniline was synthesized accordingto Method A11. 5-(Trifluoromethyl)-2-methoxyaniline was converted into5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.4-(3-Carboxyphenoxy)aniline was reacted with5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1fto afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N′-(3-carboxyphenyl)urea, which was coupled with 4-morpholinoaniline according to MethodD1c.

[0262] Entry 40: 4-(3-Carboxyphenoxy)aniline was synthesized accordingto Method A11. 5-(Trifluoromethyl)-2-methoxyaniline was converted into5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.4-(3-Carboxyphenoxy)aniline was reacted with5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1fto afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N′-(3-carboxyphenyl)urea, which was coupled with N-(2-pyridyl)piperazine according to MethodD1c.

[0263] Entry 41: 4-(3-(N-Methylcarbamoyl)phenoxy)aniline was synthesizedaccording to Method A13. According to Method C3,4-chloro-3-(trifluoromethyl)aniline was converted to the isocyanate,then reacted with 4-(3-(N-Methylcarbamoyl)phenoxy)aniline to afford theurea.

[0264] Entry 42: 4-(2-N-Methylcarbamyl-4-pyridyloxy)aniline wassynthesized according to Method A2. 4-Chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(2-N-methylcarbamyl-4-pyridyloxy)anilineaccording to Method C1a to afford the urea.

[0265] Entry 43: 4-Chloropyridine-2-carbonyl chloride HCl salt wasreacted with ammonia according to Method A2, Step 3b to form4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide wasreacted with 4-aminophenol according to Method A2, Step 4 to form4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C1a,4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.

[0266] Entry 44: 4-Chloropyridine-2-carbonyl chloride HCl salt wasreacted with ammonia according to Method A2, Step 3b to form4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide wasreacted with 3-aminophenol according to Method A2, Step 4 to form3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C1a,4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.

[0267] Entry 45: 4-Chloro-N-methyl-2-pyridinecarboxamide, which wassynthesized according to Method A2, Step 3a, was reacted with3-aminophenol according to Method A2, Step 4 to form3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C1a;4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

[0268] Entry 46: 5-(4-Aminophenoxy)isoindoline-1,3-dione was synthesizedaccording to Method A3. According to Method C1a,4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with5-(4-aminophenoxy)isoindoline-1,3-dione to afford the urea.

[0269] Entry 47: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylanilinewas synthesized according to Method A5. According to Method C1c,4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with5-(4-aminophenoxy)isoindoline-1,3-dione to afford the urea.

[0270] Entry 48: 4-(3-N-Methylsulfamoyl)phenyloxy)aniline wassynthesized according to Method A15. According to Method C1a,4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford the urea.

[0271] Entry 49: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroanilinewas synthesized according to Method A6. According to Method C1a,4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to afford theurea.

[0272] Entry 50: According to Method A2, Step 4, 5-amino-2-methylphenolwas reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had beensynthesized according to Method A2, Step 3b, to give3-(2-N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. According toMethod C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reactedwith 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to affordthe urea.

[0273] Entry 51: 4-Chloropyridine-2-carbonyl chloride was reacted withethylamine according to Method A2, Step 3b. The resulting4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenolaccording to Method A2, Step 4 to give4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. According to Method C1a,4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

[0274] Entry 52: According to Method A2, Step 4, 4-amino-2-chlorophenolwas reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had beensynthesized according to Method A2, Step 3b, to give4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. According toMethod C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reactedwith 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to affordthe urea.

[0275] Entry 53: 4-(4-Methylthiophenoxy)-1-nitrobenzene was oxidizedaccording to Method A19, Step 1 to give4-(4-methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene was reducedaccording to Method A19, Step 2 to give4-(4-methylsulfonylphenoxy)-1-aniline. According to Method C1a,4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with4-(4-methylsulfonylphenoxy)-1-aniline to afford the urea.

[0276] Entry 54: 4-Bromobenzenesulfonyl chloride was reacted withmethylamine according to Method A15, Step 1 to affordN-methyl-4-bromobenzenesulfonamide. N-Methyl-4-bromobenzenesulfonamidewas coupled with phenol according to Method A15, Step 2 to afford4-(4-(N-methylsulfamoyl)phenoxy)benzene.4-(4-(N-Methylsulfamoyl)phenoxy)benzene was converted into4-(4-(N-methylsulfamoyl)phenoxy)-1-nitrobenzene according to Method A15,Step 3. 4-(4-(N-Methylsulfamoyl)phenoxy)-1-nitrobenzene was reduced to4-(4-N-methylsulfamoyl)phenyloxy)aniline according to Method A15, Step4. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(3-N-methylsulfamoyl)phenyloxy)aniline toafford the urea.

[0277] Entry 55: 5-Hydroxy-2-methylpyridine was coupled with1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene. The methylpyridine wasoxidized according to the carboxylic acid, then esterified according toMethod A18, Step 2 to give4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene. The nitrobenzene wasreduced according the Method A18, Step 3 to give4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with4-chloro-3-(trifluoromethyl)phenyl isocyanate according to Method C1a toafford the urea.

[0278] Entry 56: 5-Hydroxy-2-methylpyridine was coupled with1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene. The methylpyridine wasoxidized according to the carboxylic acid, then esterified according toMethod A18, Step 2 to give4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene. The nitrobenzene wasreduced according the Method A18, Step 3 to give4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with4-chloro-3-(trifluoromethyl)phenyl isocyanate according to Method C1a togiveN-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(methoxycarbonyl)-5-pyridyloxy)phenyl)urea. The methyl ester was reacted with methylamine according to MethodD2 to affordN-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-5-pyridyloxy)phenyl)urea.

[0279] Entry 57:N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-aminophenyl) urea wasprepared according to Method C1d.N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-aminophenyl) urea wascoupled with mono-methyl isophthalate according to Method D1a to affordthe urea.

[0280] Entry 58:N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-aminophenyl) urea wasprepared according to Method C1d.N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-aminophenyl) urea wascoupled with mono-methyl isophthalate according to Method D1a to affordN-(4-chloro-3-(trifluoromethyl)phenyl-N′-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl)urea. According to Method D2,N-(4-chloro-3-(trifluoromethyl)phenyl-N′-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl)urea was reacted with methylamine to afford the corresponding methylamide.

[0281] Entry 59: 4-Chloropyridine-2-carbonyl chloride was reacted withdimethylamine according to Method A2, Step 3b. The resulting4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with4-aminophenol according to Method A2, Step 4 to give4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline. According to MethodC1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

[0282] Entry 60: 4-Hydroxyacetophenone was reacted with4-fluoronitrobenzene according to Method A13, Step 1 to give4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced accordingto Method 13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which wasconverted to the 4-(4-(1-(N-methoxy)iminoethyl) phenoxyaniline HCl saltaccording to Method A16. According to Method C1a,4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with4-(4-acetylphenoxy)aniline to afford the urea.

[0283] Entry 61: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesizedaccording to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene wascoupled with 4-(2-aminoethyl)morpholine according to Method A13, Step 3to give 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene.According to Method A13 Step 4,4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene wasreduced to 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)aniline.According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanatewas reacted with 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)anilineto afford the urea.

[0284] Entry 62: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesizedaccording to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene wascoupled with 1-(2-aminoethyl)piperidine according to Method A13, Step 3to give 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene.According to Method A13 Step 4,4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene was reducedto 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)aniline. According toMethod C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reactedwith 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)aniline to afford theurea.

[0285] Entry 63: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesizedaccording to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene wascoupled with tetrahydrofurfurylamine according to Method A13, Step 3 togive 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene.According to Method A13 Step 4,4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene wasreduced to 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline.According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanatewas reacted with4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline to afford theurea.

[0286] Entry 64: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesizedaccording to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene wascoupled with 2-aminomethyl-1-ethylpyrrolidine according to Method A13,Step 3 to give4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene.According to Method A13 Step 4,4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzenewas reduced to4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline.According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanatewas reacted with4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline toafford the urea.

[0287] Entry 65: 4-Chloro-N-methylpyridinecarboxamide was synthesized asdescribed in Method A2, Step 3b. The chloropyridine was reacted with4-aminothiophenol according to Method A2, Step 4 to give4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According to Method C1a,4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline to afford the urea.

[0288] Entry 66: 4-Chloropyridine-2-carbonyl chloride was reacted withisopropylamine according to Method A2, Step 3b. The resulting4-chloro-N-isopropyl-2-pyridinecarboxamide was reacted with4-aminophenol according to Method A2, Step 4 to give4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline. According to MethodC1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

[0289] Entry 67:N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-ethoxycarbonylphenyl) ureawas synthesized according to Method C1e.N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-ethoxycarbonylphenyl) ureawas saponified according to Method D3 to giveN-(4-chloro-3-(trifluoromethyl)phenyl-N′-(4-carboxyphenyl) urea.N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-carboxyphenyl) urea wascoupled with 3-methylcarbamoylaniline according to Method Dlb to giveN-(4-chloro-3-(trifluoromethyl)phenyl-N′-(4-(3-methylcarbamoylphenyl)carbamoylphenyl)urea.

[0290] Entry 68: 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione wassynthesized according to Method A9. According to Method C1a,4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione to afford the urea.

[0291] Entry 69: 4-Chloro-N-methylpyridinecarboxamide was synthesized asdescribed in Method A2, Step 3b. The chloropyridine was reacted with3-aminothiophenol according to Method A2, Step 4 to give3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According to Method C1a,4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline to afford the urea.

[0292] Entry 70:4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline wassynthesized according to Method A10. According to Method C1a,4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to affordthe urea.

[0293] Entry 71: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline wassynthesized according to Method A14.4-Chloro-3-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1a toafford the urea.N-(4-Chloro-3-(trifluoromethyl)phenyl)-N′-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea was saponified according to Method D4, Step 1, and thecorresponding acid was coupled with 4-(2-aminoethyl)morpholine to affordthe amide.

[0294] Entry 72: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline wassynthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)anilineaccording to Method C1a to afford the urea.N-(5-(Trifluoromethyl)-2methoxyphenyl)-N′-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea was saponified according to Method D4, Step 1, and thecorresponding acid was coupled with methylamine according to Method D4,Step 2 to afford the amide.

[0295] Entry 73: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline wassynthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)anilineaccording to Method C1a to afford the urea.N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N′-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea was saponified according to Method D4, Step 1, and thecorresponding acid was coupled with N,N-dimethylethylenediamineaccording to Method D4, Step 2 to afford the amide.

[0296] Entry 74: 4-Chloropyridine-2-carbonyl chloride HCl salt wasreacted with 2-hydroxyethylamine according to Method A2, Step 3b to form4-chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide.4-Chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide wasreacted with triisopropylsilyl chloride, followed by 4-aminophenolaccording to Method A17 to form4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline.According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanatewas reacted with 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline to affordN-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyphenyl) urea.

[0297] Entry 75: 4-(3-Carboxyphenoxy)aniline was synthesized accordingto Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reactedwith 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1fto afford the urea, which was coupled with 3-aminopyridine according toMethod D1c.

[0298] Entry 76: 4-(3-Carboxyphenoxy)aniline was synthesized accordingto Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reactedwith 4-(3-carboxyphenoxy)aniline according to Method C1f to afford theurea, which was coupled with N-(4-acetylphenyl)piperazine according toMethod D1c.

[0299] Entry 77: 4-(3-Carboxyphenoxy)aniline was synthesized accordingto Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reactedwith 4-(3-carboxyphenoxy)aniline according to Method C1f to afford theurea, which was coupled with 4-fluoroaniline according to Method D1c.

[0300] Entry 78: 4-(3-Carboxyphenoxy)aniline was synthesized accordingto Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reactedwith 4-(3-carboxyphenoxy)aniline according to Method C1f to afford theurea, which was coupled with 4-(dimethylamino)aniline according toMethod D1c.

[0301] Entry 79: 4-(3-Carboxyphenoxy)aniline was synthesized accordingto Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reactedwith 4-(3-carboxyphenoxy)aniline according to Method C1f to afford theurea, which was coupled with N-phenylethylenediamine according to MethodD1c.

[0302] Entry 80: 4-(3-Carboxyphenoxy)aniline was synthesized accordingto Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reactedwith 4-(3-carboxyphenoxy)aniline according to Method C1f to afford theurea, which was coupled with 2-methoxyethylamine according to MethodD1c.

[0303] Entry 81: 4-(3-Carboxyphenoxy)aniline was synthesized accordingto Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reactedwith 4-(3-carboxyphenoxy)aniline according to Method C1f to afford theurea, which was coupled with 5-amino-2-methoxypyridine according toMethod D1c.

[0304] Entry 82: 4-(3-Carboxyphenoxy)aniline was synthesized accordingto Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reactedwith 4-(3-carboxyphenoxy)aniline according to Method C1f to afford theurea, which was coupled with 4-morpholinoaniline according to MethodD1c.

[0305] Entry 83: 4-(3-Carboxyphenoxy)aniline was synthesized accordingto Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reactedwith 4-(3-carboxyphenoxy)aniline according to Method C1f to afford theurea, which was coupled with N-(2-pyridyl)piperazine according to MethodD1c.

[0306] Entry 84: 4-Chloropyridine-2-carbonyl chloride HCl salt wasreacted with 2-hydroxyethylamine according to Method A2, Step 3b to form4-chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide.4-Chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide wasreacted with triisopropylsilyl chloride, followed by 4-aminophenolaccording to Method A17 to form4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline.According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanatewas reacted with4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline togiveN-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyphenyl)urea. The urea was deprotected according to Method D5 to affordN-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(4-(2-(N-(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl)urea.

[0307] Entry 85: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline wassynthesized according to Method A2. 4-Bromo-3-(trifluoromethyl)anilinewas converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate accordingto Method B1. According to Method C1a, 4-bromo-3-(trifluoromethyl)phenylisocyanate was reacted with4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

[0308] Entry 86: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroanilinewas synthesized according to Method A6.4-Bromo-3-(trifluoromethyl)aniline was converted into4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanatewas reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroanilineto afford the urea.

[0309] Entry 87: According to Method A2, Step 4, 4-amino-2-chlorophenolwas reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had beensynthesized according to Method A2, Step 3b, to give4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline.4-Bromo-3-(trifluoromethyl)aniline was converted into4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanatewas reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroanilineto afford the urea.

[0310] Entry 88: 4-Chloropyridine-2-carbonyl chloride was reacted withethylamine according to Method A2, Step 3b. The resulting4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenolaccording to Method A2, Step 4 to give4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline.4-Bromo-3-(trifluoromethyl)aniline was converted into4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanatewas reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to affordthe urea.

[0311] Entry 89: 4-Chloro-N-methyl-2-pyridinecarboxamide, which wassynthesized according to Method A2, Step 3a, was reacted with3-aminophenol according to Method A2, Step 4 to form3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline.4-Bromo-3-(trifluoromethyl)aniline was converted into4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanatewas reacted with 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline toafford the urea.

[0312] Entry 90: According to Method A2, Step 4, 5-amino-2-methylphenolwas reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had beensynthesized according to Method A2, Step 3b, to give3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline.4-Bromo-3-(trifluoromethyl)aniline was converted into4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanatewas reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylanilineto afford the urea.

[0313] Entry 91: 4-Chloropyridine-2-carbonyl chloride was reacted withdimethylamine according to Method A2, Step 3b. The resulting4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with4-aminophenol according to Method A2, Step 4 to give4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline.4-Bromo-3-(trifluoromethyl)aniline was converted into4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanatewas reacted with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline toafford the urea.

[0314] Entry 92: 4-Chloro-N-methylpyridinecarboxamide was synthesized asdescribed in Method A2, Step 3b. The chloropyridine was reacted with4-aminothiophenol according to Method A2, Step 4 to give4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline.4-Bromo-3-(trifluoromethyl)aniline was converted into4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanatewas reacted with 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline to affordthe urea.

[0315] Entry 93: 4-Chloro-N-methylpyridinecarboxamide was synthesized asdescribed in Method A2, Step 3b. The chloropyridine was reacted with3-aminothiophenol according to Method A2, Step 4 to give3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline.4-Bromo-3-(trifluoromethyl)aniline was converted into4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanatewas reacted with 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline to affordthe urea.

[0316] Entry 94:4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline wassynthesized according to Method A10. 4-Bromo-3-(trifluoromethyl)anilinewas converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanateaccording to Method B1. According to Method C1a,4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to affordthe urea.

[0317] Entry 95: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline wassynthesized according to Method A2.4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized accordingto Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline wasconverted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanateaccording to Method B1. According to Method C1a,4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

[0318] Entry 96: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroanilinewas synthesized according to Method A6.4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized accordingto Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline wasconverted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanateaccording to Method B1. According to Method C1a,4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline afford the urea.

[0319] Entry 97: According to Method A2, Step 4, 4-amino-2-chlorophenolwas reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had beensynthesized according to Method A2, Step 3b, to give4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline.4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized accordingto Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline wasconverted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanateaccording to Method B1. According to Method C1a,4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford theurea.

[0320] Entry 98: 4-Chloro-N-methyl-2-pyridinecarboxamide, which wassynthesized according to Method A2, Step 3a, was reacted with3-aminophenol according to Method A2, Step 4 to form3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline.4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized accordingto Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline wasconverted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanateaccording to Method B1. According to Method C1a,4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate as was reactedwith 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

[0321] Entry 99: 4-Chloropyridine-2-carbonyl chloride was reacted withethylamine according to Method A2, Step 3b. The resulting4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenolaccording to Method A2, Step 4 to give4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline.4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized accordingto Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline wasconverted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanateaccording to Method B1. According to Method C1a,4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

[0322] Entry 100: 4-Chloropyridine-2-carbonyl chloride was reacted withdimethylamine according to Method A2, Step 3b. The resulting4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with4-aminophenol according to Method A2, Step 4 to give4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline.4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized accordingto Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline wasconverted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanateaccording to Method B1. According to Method C1a,4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

[0323] Entry 101: 4-Chloro-N-methyl-2-pyridinecarboxamide, which wassynthesized according to Method A2, Step 3a, was reacted with3-aminophenol according to Method A2, Step 4 to form3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline.2-Amino-3-methoxynaphthalene was synthesized as described Method A1.According to Method C3, 2-amino-3-methoxynaphthalene was reacted withbis(trichloromethyl) carbonate followed by3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to form the urea.

[0324] Entry 102: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline wassynthesized according to Method A2.5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline was synthesized accordingto Method A4. 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline was reactedwith CDI followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)anilineaccording to Method C2d to afford the urea.

[0325] Entry 103: 4-Chloro-N-methyl-2-pyridinecarboxamide wassynthesized according to Method A2, Step 3b.4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with 4-aminophenolaccording to Method A2, Step 4 using DMAC in place of DMF to give4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2b,reaction of 3-amino-2-methoxyquinoline with CDI followed by4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline affordedbis(4-(2-(N-methylcarbamoyl)-4-pyridlyoxy)phenyl)urea.

[0326] Listed in the Tables below are compounds which have beensynthesized according to the Detailed Experimental Procedures givenabove:

Tables

[0327] The compounds listed in Tables 1-6 below were synthesizedaccording to the general methods shown above, and the more detailedexemplary procedures are in the entry listings above andcharacterizations are indicated in the tables. TABLE 13-tert-Butylphenyl Ureas

TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (° C.) (min.) R_(f)System [Source] Method 1

0.22 50% EtOAc/ 50% hexane 418 (M + H) +(HPLC ES-MS) A13 C3 2

0.58 50% EtOAc/ 50% hexane 403 (M + H) +(HPLC ES-MS) A13 C3 3

133-135 0.68 100% EtOAc 448 (M + H) +(FAB) A8 C2d

[0328] TABLE 2 5-tert-Butyl-2-methoxyphenyl Ureas

TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (° C.) (min.) R_(f)System [Source] Method 4

5.93 448 (M + H) +(HPLC ES-MS) A13 B1 C1a 5

120-122 0.67 100% EtOAc 478 (M + H) +(FAB) A8 C2d 6

0.40 50% EtOAc/ 50% hexane 460 (M + H) +(HPLC ES-MS) A3 C2d 7

0.79 50% EtOAc/ 50% hexane 446 (M + H) +(HPLC ES-MS) A12 C2d

[0329] TABLE 3 5-(Trifluoromethyl)-2-methoxyphenyl Ureas

TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (° C.) (min.) R_(f)System [Source] Method 8

250 (dec) 460 (M + H) +(FAB) A13 C2a 9

206-208 0.54 10% MeOH/ 90% CH2Cl2 446 (M + H) +(HPLC ES-MS) A3 step 2,A8 step 4, B1, C1a 10

0.33 50% EtOAc/ 50% pet ether 445 (M + H) +(HPLC ES-MS) A13 C3 11

0.20 2% Et3N/ 98% EtOAc 461 (M + H) +(HPLC ES-MS) A2 C4 12

0.27 1% Et3N/ 99% EtOAc 447 (M + H) +(HPLC ES-MS) A2 C4 13

0.62 100% EtOAc 461 (M + H) +(FAB) A2 C2a 14

114-117 0.40 1% Et3N/ 99% EtOAc 447 (M + H) +(FAB) A2 C4 15

232-235 0.54 100% EtOAc 490 (M + H) +(FAB) A8 C2d 16

210-213 0.29 5% MeOH/ 45% EtOAc/ 50% pet ether 475 (M + H) +(HPLC ES-MS)A5 B1 C1c 17

187-188 0.17 50% EtOAc/ 50% pet ether 495 (M + H) +(HPLC ES-MS) A6 B1C1a 18

0.48 100% EtOAc 475 (M + H) +(HPLC ES-MS) A2 step 4, B1 C1a 19

194-196 0.31 5% MeOH/ 45% EtOAc/ 50% pet ether 475 (M + H) +(HPLC ES-MS)A2 B1 C1a 20

214-216 0.25 5% MeOH/ 45% EtOAc/ 50% pet ether 495 (M + H) +(HPLC ES-MS)A2 C1a 21

208-210 0.30 50% EtOAc/ 50% hexane 481 (M + H) +(HPLC ES-MS) A19 C2a 22

188-190 0.30 70% EtOAc/ 50% hexane 447 (M + H) +(HPLC ES-MS) A15, step4, C1a 23

0.50 70% EtOAc/ 30% hexane 472 (M + H) +(FAB) A3 B1 C1a 24

203-205 0.13 100% EtOAc 479 (M + H) +(HPLC ES-MS) A2 B1 C1a 25

0.09 75% EtOAc/ 25% hexane 458 (M + H) +(HPLC ES-MS) A12 C2d 26

169-171 0.67 50% EtOAc/ 50% pet ether 474 (M + H) +(HPLC ES-MS) A13 step1, A13 step 4, A16, B1 C1a 27

218-219 0.40 50% EtOAc/ 50% pet ether 477 (M + H) +(HPLC ES-MS) A2 step3b, A2 step 4, B1, C1a 28

212-214 0.30 40% EtOAc/ 60% hexane A9 B1 C1a 29

0.33 50% EtOAc/ 50% pet ether 474 (M + H) +(HPLC ES-MS) A2 step 3b, A2step 4, B1, C1a 30

210-211 A2 B1 C1a 31

210-204 0.43 10% MeOH/ CH2Cl2 A14 B1 C1a D4 32

247-249 0.57 10% MeOH/ CH2Cl2 A14 B1 C1a D4 33

217-219 0.07 10% MeOH/ CH2Cl2 A14 B1 C1a D4 34

0.11 70% EtOAc/ 30% hexane A11 B1 C1f D1c 35

0.38 70% EtOAc/ 30% hexane A11 B1 C1f D1c 36

0.77 70% EtOAc/ 30% hexane A11 B1 C1f D1c 37

0.58 70% EtOAc/ 30% hexane A11 B1 C1f D1c 38

0.58 70% EtOAc/ 30% hexane A11 B1 C1f D1c 39

0.17 70% EtOAc/ 30% hexane A11 B1 C1f D1c 40

0.21 70% EtOAc/ 30% hexane A11 B1 C1f D1c

[0330] TABLE 4 3-(Trifluoromethyl)-4-chlorophenyl Ureas

TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (° C.) (min.) R_(f)System [Source] Method 41

163-165 0.08 50% EtOAc/ 50% pet ether 464 (M + H) +(HPLC ES-MS) A13 C342

215 0.06 50% EtOAc/ 50% pet ether 465 (M + H) +(HPLC ES-MS) A2 C1a 43

0.10 50% EtOAc/ 50% pet ether 451 (M + H) +(HPLC ES-MS) A2 C1a 44

0.25 30% EtOAc/ 70% pet ether 451 (M + H) +(HPLC ES-MS) A2 C1a 45

0.31 30% EtOAc/ 70% pet ether 465 (M + H) +(HPLC ES-MS) A2 C1a 46

176-179 0.23 40% EtOAc/ 60% hexane 476 (M + H) +(FAB) A3 C1a 47

0.29 5% MeOH/ 45% EtOAc/ 50% pet ether 478 (M + H) +(HPLC ES-MS) A5 C1c48

206-209 A15 C1a 49

147-151 0.22 50% EtOAc/ 50% pet ether 499 (M + H) +(HPLC ES-MS) A6 C1a50

0.54 100% EtOAc 479 (M + H) +(HPLC ES-MS) A2 C1a 51

187-189 0.33 5% MeOH/ 45% EtOAc/ 50% pet ether 479 (M + H) +(HPLC ES-MS)A2 C1a 52

219 0.18 5% MeOH/ 45% EtOAc/ 50% pet ether 499 (M + H) +(HPLC ES-MS) A2C1a 53

246-248 0.30 50% EtOAc/ 50% hexane 485 (M + H) +(HPLC ES-MS) A19, C1a 54

196-200 0.30 70% EtOAc/ 30% hexane) 502 (M + H) +(HPLC ES-MS) A15 C1a 55

228-230 0.30 30% EtOAc/ 70% CH2Cl2 466 (M + H) +(HPLC ES-MS) 56

238-245 57

221-222 0.75 80% EtOAc/ 20% hexane 492 (M + H) +(FAB) C1d D1a 58

247 0.35 100% EtOAc C1d D1a D2 59

198-200 0.09 100% EtOAc 479 (M + H) +(HPLC ES-MS) A2 C1a 60

158-160 0.64 50% EtOAc/ 50% pet ether 61

195-197 0.39 10% MeOH/ CH2Cl2 A13 C1a 62

170-172 0.52 10% MeOH/ CH2Cl2 A13 C1a 63

168-171 0.39 10% MeOH/ CH2Cl2 A13 C1a 64

176-177 0.35 10% MeOH/ CH2Cl2 A13 C1a 65

130-133 487 (M + H) +(HPLC ES-MS) A2 B1 C1a 66

155 A2 C1a 67

225-229 0.23 100% EtOAc C1e D3 D1b 68

234-236 0.29 40% EtOAc/ 60% hexane A9 C1a 69

0.48 50% EtOAc/ 50% pet ether 481 (M + H) +(HPLC ES-MS) 70

0.46 5% MeOH/ 95% CH2Cl2 564 (M + H) +(HPLC ES-MS) A10 C1a 71

199-201 0.50 10% MeOH/ CH2Cl2 A14 C1a D4 72

235-237 0.55 10% MeOH/ CH2Cl2 A14 C1a D4 73

200-201 0.21 50% MeOH/ CH2Cl2 A14 C1a D4 74

145-148 75

0.12 70% EtOAc/ 30% hexane 527 (M + H) +(HPLC ES-MS) A11 C1f D1c 76

0.18 70% EtOAc/ 30% hexane A11 C1f D1c 77

0.74 70% EtOAc/ 30% hexane A11 C1f D1c 78

0.58 70% EtOAc/ 30% hexane A11 C1f D1c 79

0.47 70% EtOAc/ 30% hexane 569 (M + H) +(HPLC ES-MS) A11 C1f D1c 80

0.18 70% EtOAc/ 30% hexane 508 (M + H) +(HPLC ES-MS) A11 C1f D1c 81

0.58 70% EtOAc/ 30% hexane 557 (M + H) +(HPLC ES-MS) A11 C1f D1c 82

0.37 70% EtOAc/ 30% hexane 611 (M + H) +(HPLC ES-MS) A11 C1f D1c 83

0.19 70% EtOAc/ 30% hexane A11 C1f D1c 84

179-183 A2 A17

[0331] TABLE 5 3-(Trifluoromethyl)-4-bromophenyl Ureas

TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (° C.) (min.) R_(f)System [Source] Method 85

186-187 0.13 50% EtOAc/ 50% pet ether 509 (M + H) +(HPLC ES-MS) A2 B1C1a 86

150-152 0.31 50% EtOAc/ 50% pet ether 545 (M + H) +(HPLC ES-MS) A6 B1C1a 87

217-219 0.16 50% EtOAc/ 50% pet ether 545 (M + H) +(HPLC ES-MS) A2 B1C1a 88

183-184 0.31 50% EtOAc/ 50% pet ether 525 (M + H) +(HPLC ES-MS) A2 B1C1a 89

0.21 50% EtOAc/ 50% pet ether 511 (M + H) +(HPLC ES-MS) A2 B1 C1a 90

0.28 50% EtOAc/ 50% pet ether 525 (M + H) +(HPLC ES-MS) A2 B1 C1a 91

214-216 0.28 50% EtOAc/ 50% pet ether 522 (M + H) +(HPLC ES-MS) A2 B1C1a 92

0.47 50% EtOAc/ 50% pet ether 527 (M + H) +(HPLC ES-MS) A2 step 3b, A2step 4, B1, C1a 93

0.46 50% EtOAc/ 50% pet ether 527 (M + H) +(HPLC ES-MS) A2 step 3b, A2step 4, B1, C1a 94

145-150 0.41 5% MeOH/ 95% CH2Cl2 A10 B1 C1a

[0332] TABLE 6 5-(Trifluoromethyl)-4-chloro-2-methoxyphenyl Ureas

TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (° C.) (min.) R_(f)System [Source] Method 95

140-144 0.29 5% MeOH/ 45% EtOAc/ 50% pet ether 495 (M + H) +(HPLC ES-MS)A2 A7 B1 C1a 96

244-245 0.39 5% MeOH/ 45% EtOAc/ 50% pet ether 529 (M + H) +(HPLC ES-MS)A6 A7 B1 C1a 97

220-221 0.25 5% MeOH/ 45% EtOAc/ 50% pet ether 529 (M + H) +(HPLC ES-MS)A2 A7 B1 C1a 98

0.27 5% MeOH/ 45% EtOAc/ 50% pet ether 495 (M + H) +(HPLC ES-MS) A2 A7B1 C1a 99

180- 0.52 5% MeOH/ 45% EtOAc/ 50% pet ether 509 (M + H) +(HPLC ES-MS) A2A7 B1 C1a 100

162-165 A2 A7 B1 C1a

[0333] TABLE 7 Additional Ureas TLC Mass mp HPLC TLC Solvent Spec.Synth. Entry R (° C.) (min.) R_(f) System [Source] Method 101

162-165 A1 A2 C3 102

0.10 50% EtOAc/ 50% hexane 442 (M + H) +(HPLC ES-MS) A2 A4 C2d 103

125-130 0.24 40% EtOAc/ 60% hexane 512 (M + H) +(FAB) A2 C2b

BIOLOGICAL EXAMPLES

[0334] In Vitro raf Kinase Assay:

[0335] In an in vitro kinase assay, raf was incubated with MEK in 20 mMTris-HCl , pH 8.2 containing 2 mM 2-mercaptoethanol and 100 mM NaCl.This protein solution (20 μL) was mixed with water (5 μL) or withcompounds diluted with distilled water from 10 mM stock solutions ofcompounds dissolved in DMSO. The kinase reaction was initiated by adding25 μL [λ-³³P]ATP (1000-3000 dpm/pmol) in 80 mM Tris-HCl, pH 7.5, 120 mMNaCl, 1.6 mM DTT, 16 mM MgCl₂. The reaction mixtures were incubated at32° C., usually for 22 min. Incorporation of ³³P into protein wasassayed by harvesting the reaction onto phosphocellulose mats, washingaway free counts with a 1% phosphoric acid solution and quantitatingphosphorylation by liquid scintillation counting. For high throughputscreening, 10 μM ATP and 0.4 μM MEK was used. In some experiments, thekinase reaction was stopped by adding an equal amount of Laemmli samplebuffer. Samples were boiled 3 min and the proteins resolved byelectrophoresis on 7.5% Laemmli gels. Gels were fixed, dried and exposedto an imaging plate (Fuji). Phosphorylation was analyzed using a FujixBio-Imaging Analyzer System.

[0336] All compounds exemplified displayed IC₅₀s of between 1 nM and 10μM.

[0337] Cellular Assay:

[0338] For in vitro growth assay, human tumor cell lines, including butnot limited to HCT116 and DLD-1, containing mutated K-ras genes wereused in standard proliferation assays for anchorage dependent growth onplastic or anchorage independent growth in soft agar. Human tumor celllines were obtained from ATCC (Rockville Md.) and maintained in RPMIwith 10% heat inactivated fetal bovine serum and 200 mM glutamine. Cellculture media and additives were obtained from Gibco/BRL (Gaithersburg,Md.) except for fetal bovine serum (JRH Biosciences, Lenexa, Kans.). Ina standard proliferation assay for anchorage dependent growth, 3×10³cells were seeded into 96-well tissue culture plates and allowed toattach overnight at 37° C. in a 5% CO₂ incubator. Compounds weretitrated in media in dilution series and added to 96-well cell cultures.Cells were allowed to grow 5 days typically with a feeding of freshcompound containing media on day three. Proliferation was monitored bymeasuring metabolic activity with standard XTT colorimetric assay(Boehringer Mannheim) measured by standard ELISA plate reader at OD490/560, or by measuring ³H-thymidine incorporation into DNA followingan 8 h culture with 1 μCu ³H-thymidine, harvesting the cells onto glassfiber mats using a cell harvester and measuring ³H-thymidineincorporation by liquid scintillant counting.

[0339] For anchorage independent cell growth, cells were plated at 1×10³to 3×10³ in 0.4% Seaplaque agarose in RPMI complete media, overlaying abottom layer containing only 0.64% agar in RPMI complete media in24-well tissue culture plates. Complete media plus dilution series ofcompounds were added to wells and incubated at 37° C. in a 5% CO₂incubator for 10-14 days with repeated feedings of fresh mediacontaining compound at 3-4 day intervals. Colony formation was monitoredand total cell mass, average colony size and number of colonies werequantitated using image capture technology and image analysis software(Image Pro Plus, media Cybernetics).

[0340] In Vivo Assay:

[0341] An in vivo assay of the inhibitory effect of the compounds ontumors (e.g., solid cancers) mediated by raf kinase can be performed asfollows:

[0342] CDI nu/nu mice (6-8 weeks old) are injected subcutaneously intothe flank at 1×10⁶ cells with human colon adenocarcinoma cell line. Themice are dosed i.p., i.v. or p.o. at 10, 30, 100, or 300 mg/Kg beginningon approximately day 10, when tumor size is between 50-100 mg. Animalsare dosed for 14 consecutive days once a day; tumor size was monitoredwith calipers twice a week.

[0343] The inhibitory effect of the compounds on raf kinase andtherefore on tumors (e.g., solid cancers) mediated by raf kinase canfurther be demonstrated in vivo according to the technique of Monia etal. (Nat. Med. 1996, 2, 668-75).

[0344] The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

[0345] From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound of Formula I: A—D—B  (I) or apharmaceutically acceptable salt thereof, wherein D is —NH—C(O)—NH—, Ais a substituted moiety of up to 40 carbon atoms of the formula:—L—(M—L¹)_(q), where L is a 5 or 6 membered cyclic structure bounddirectly to D, L¹ comprises a substituted cyclic moiety having at least5 members, M is a bridging group having at least one atom, q is aninteger of from 1-3; and each cyclic stricture of L and L¹ contains 0-4members of the group consisting of nitrogen, oxygen and sulfur, and B isa substituted or unsubstituted, up to tricyclic aryl or heteroarylmoiety of up to 30 carbon atoms with at least one 6-member cyclicstructure bound directly to D containing 0-4 members of the groupconsisting of nitrogen, oxygen and sulfur, wherein L¹ is substituted byat least one substituent selected from the group consisting of—SO₂R_(x), —C(O)R_(x) and —C(NR_(y))R_(z), R_(y) is hydrogen or a carbonbased moiety of up to 24 carbon atoms optionally containing heteroatomsselected from N, S and O and optionally halosubstituted, up to per halo,R_(z) is hydrogen or a carbon based moiety of up to 30 carbon atomsoptionally containing heteroatoms selected from N, S and O andoptionally substituted by halogen, hydroxy and carbon based substituentsof up to 24 carbon atoms, which optionally contain heteroatoms selectedfrom N, S and O and are optionally substituted by halogen; R_(x) isR_(z) or NR_(a)R_(b) where R_(a) and R_(b) are a) independentlyhydrogen, a carbon based moiety of up to 30 carbon atoms optionallycontaining heteroatoms selected from N, S and O and optionallysubstituted by halogen, hydroxy and carbon based substituents of up to24 carbon atoms, which optionally contain heteroatoms selected from N, Sand O and are optionally substituted by halogen, or —OSi(R_(f))₃ whereR_(f) is hydrogen or a carbon based moiety of up to 24 carbon atomsoptionally containing heteroatoms selected from N, S and O andoptionally substituted by halogen, hydroxy and carbon based substituentsof up to 24 carbon atoms, which optionally contain heteroatoms selectedfrom N, S and O and are optionally substituted by halogen; or b) R_(a)and R_(b) together form a 5-7 member heterocyclic stricture of 1-3heteroatoms selected from N, S and O, or a substituted 5-7 memberheterocyclic structure of 1-3 heteroatoms selected from N, S and Osubstituted by halogen, hydroxy or carbon based substituents of up to 24carbon atoms, which optionally contain heteroatoms selected from N, Sand O and are optionally substituted by halogen; or c) one of R_(a) orR_(b) is —C(O)—, a C₁-C₅ divalent alkylene group or a substituted C₁-C₅divalent alkylene group bound to the moiety L to form a cyclic structurewith at least 5 members, wherein the substituents of the substitutedC₁-C₅ divalent alkylene group are selected from the group consisting ofhalogen, hydroxy, and carbon based substituents of up to 24 carbonatoms, which optionally contain heteroatoms selected from N, S and O andare optionally substituted by halogen; where B is substituted, L issubstituted or L¹ is additionally substituted, the substituents areselected from the group consisting of halogen, up to per-halo, and Wn,where n is 0-3; wherein each W is independently selected from the groupconsisting of —CN, —CO₂R⁷, —C(O)NR⁷R⁷, —C(O)—R⁷, —NO₂, —OR⁷, —SR⁷,—NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, —Q—Ar, and carbon based moieties of upto 24 carbon atoms, optionally containing heteroatoms selected from N, Sand O and optionally substituted by one or more substituentsindependently selected from the group consisting of —CN, —CO₂R⁷,—C(O)R⁷, —C(O)NR⁷R⁷, —OR⁷, —SR⁷, —NR⁷R⁷, —NO₂, —NR⁷C(O)R⁷, —NR⁷C(O)OR⁷and halogen up to per-halo; with each R⁷ independently selected from Hor a carbon based moiety of up to 24 carbon atoms, optionally containingheteroatoms selected from N, S and O and optionally substituted byhalogen, wherein Q is —O—, —S—, —N(R⁷)—, —(CH₂)_(m)—, —C(O)—, —CH(OH)—,—(CH₂)_(m)O—, —(CH₂)_(m)S—, —(CH₂)_(m)N(R⁷)—, —O(CH₂)_(m)—CHX^(a),—CX^(a) ₂—, —S—(CH₂)_(m)— and —N(R⁷)(CH₂)_(m)—, where m=1-3, and X^(a)is halogen; and Ar is a 5- or 6-member aromatic structure containing 0-2members selected from the group consisting of nitrogen, oxygen andsulfur, which is optionally substituted by halogen, up to per-halo, andoptionally substituted by Z_(n1), wherein n1 is 0 to 3 and each Z isindependently selected from the group consisting of —CN, —CO₂R⁷,—C(O)R⁷, —C(O)NR⁷R⁷, —NO₂, —OR⁷, —SR⁷—NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷,and a carbon based moiety of up to 24 carbon atoms, optionallycontaining heteroatoms selected from N, S and O and optionallysubstituted by one or more substituents selected from the groupconsisting of —CN, —CO₂R⁷, —COR⁷, —C(O)NR⁷R⁷, —OR⁷, —SR⁷, —NO₂, —NR⁷R⁷,—NR⁷C(O)R⁷, and —NR⁷C(O)OR⁷, with R⁷ as defined above.
 2. A compound asin claim 1 wherein: R_(y) is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₃₋₁₀cycloalkyl having 0-3 heteroatoms, C₂₋₁₀ alkenyl, C₁₋₁₀ alkenoyl, C₆₋₁₂aryl, C₃₋₁₂ hetaryl having 1-3 heteroatoms selected from N, S and O,C₇₋₂₄ aralkyl, C₇₋₂₄ alkaryl, substituted C₁₋₁₀ alkyl, substituted C₁₋₁₀alkyl, substituted C₁₋₁₀ alkoxy, substituted C₃₋₁₀ cycloalkyl having 0-3heteroatoms selected from N, S and O, substituted C₆-C₁₄ aryl,substituted C₃₋₁₂ hetaryl having 1-3 heteroatoms selected from N, S andO, substituted C₇₋₂₄ alkaryl or substituted C₇-C₂₄ aralkyl, where R_(y)is a substituted group, it is substituted by halogen up to per halo,R_(z) is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₃₋₁₀ cycloalkyl having0-3 heteroatom, C₂₋₁₀ alkenyl, C₁₋₁₀ alkenoyl, C₆₋₁₂ aryl, C₃-C₁₂hetaryl having 1-3 heteroatoms selected from, S, N and O, C₇₋₂₄ alkaryl, C₇₋₂₄ aralkyl, substituted C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkoxy,substituted C₆-C₁₄ aryl, substituted C₃-C₁₀ cycloalkyl having 0-3heteroatoms selected from S, N and O, substituted C₃₋₁₂ hetaryl having1-3 heteroatoms selected from S, N and O, substituted C₇₋₂₄ alkaryl orsubstituted C₇-C₂₄ aralkyl where R_(z) is a substituted group, it issubstituted by halogen up to per halo, hydroxy, C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl having 0-3 heteroatoms selected from O, S and N, C₃₋₁₂hetaryl having 1-3 heteroatoms selected from N, S and O, C₁₋₁₀ alkoxy,C₆₋₁₂ aryl, C₁₋₆ halo substituted alkyl up to per halo alkyl, C₆-C₁₂halo substituted aryl up to per halo aryl, C₃-C₁₂ halo substitutedcycloalkyl up to per halo cycloalkyl having 0-3 heteroatoms selectedfrom N, S and O, halo substituted C₃-C₁₂ hetaryl up to per halo hetarylhaving 1-3 heteroatoms selected from O, N and S, halo substituted C₇-C₂₄aralkyl up to per halo aralkyl, halo substituted C₇-C₂₄ alkaryl up toper halo alkaryl, and —C(O)R_(g), R_(a) and R_(b) are, a) independentlyhydrogen, a carbon based moiety selected from te group consisting ofC₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₃₋₁₀ cycloalkyl, C₂₋₁₀ alkenyl, C₁₋₁₀alkenoyl, C₆₋₁₂ aryl, C₃₋₁₂ hetaryl having 1-3 heteroatoms selected fromO, N and S, C₃₋₁₂ cycloalkyl having 0-3 heteroatoms selected from N, Sand O, C₇₋₂₄ aralkyl, C₇-C₂₄ alkaryl, substituted C₁₋₁₀ alkyl,substituted C₁₋₁₀ alkoxy, substituted C₃₋₁₀ cycloalkyl, having 0-3heteroatoms selected from N, S and O, substituted C₆₋₁₂ aryl,substituted C₃₋₁₂ hetaryl having 1-3 heteroatoms selected from N, S andO, substituted C₇₋₂₄ aralkyl, substituted C₇₋₂₄ alkaryl, where R_(a) andR_(b) are a substituted group, they are substituted by halogen up to perhalo, hydroxy, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl having 0-3 heteroatomsselected from O, S and N, C₃₋₁₂ hetaryl having 1-3 heteroatoms selectedfrom N, S and O, C₁₋₁₀ alkoxy, C₆₋₁₂ aryl, C₁₋₆ halo substituted alkylup to per halo alkyl, C₆-C₁₂ halo substituted aryl up to per halo aryl,C₃-C₁₂ halo substituted cycloalkyl having 0-3 heteroatoms selected fromN, S and O, up to per halo cycloalkyl, halo substituted C₃-C₁₂ hetarylup to per halo heteraryl, halo substituted C₇-C₂₄ aralkyl up to per haloaralkyl, halo substituted C₇-C₂₄ alkaryl up to per halo alkaryl, and—C(O)R_(g); or —OSi(R_(f))₃ where R_(f) is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, C₃-C₁₀ cycloalkyl having 0-3 heteroatoms selected from O, S andN, C₆₋₁₂ aryl, C₃-C₁₂ hetaryl having 1-3 heteroatoms selected from O, Sand N, C₇₋₂₄ aralkyl, substituted C₁₋₁₀ alkyl, substituted C₁-C₁₀alkoxy, substituted C₃-C₁₂ cycloalkyl having 0-3 heteroatoms selectedfrom O, S and N, substituted C₃-C₁₂ heteraryl having 1-3 heteroatomsselected from O, S, and N, substituted C₆₋₁₂ aryl, and substituted C₇₋₂₄alkaryl, where R_(f) is a substituted group it is substituted halogen upto per halo, hydroxy, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl having 0-3heteroatoms selected from O, S and N, C₃₋₁₂ hetaryl having 1-3heteroatoms selected from N, S and O, C₁₋₁₀ alkoxy, C₆₋₁₂ aryl, C₇-C₂₄alkaryl, C₇-C₂₄ aralkyl, C₁₋₆ halo substituted alkyl up to per haloalkyl, C₆-C₁₂ halo substituted aryl tip to per halo aryl, C₃-C₁₂ halosubstituted cycloalkyl having 0-3 heteroatoms selected from N, S and O,up to per halo cycloalkyl, halo substituted C₃-C₁₂ hetaryl up to perhalo heteraryl, halo substituted C₇-C₂₄ aralkyl up to per halo aralkyl,halo substituted C₇-C₂₄ alkaryl up to per halo alkaryl, and —C(O)R_(g),or b) R_(a) and R_(b) together form a 5-7 member heterocyclic structureof 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 memberheterocyclic structure of 1-3 heteroatoms selected from N, S and O withsubstituents selected from the group consisting of halogen up to perhalo, hydroxy, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl having 0-3 heteroatomsselected from O, S and N, C₃₋₁₂ hetaryl having 1-3 heteroatoms selectedfrom N, S and O, C₁₋₁₀ alkoxy, C₆₋₁₂ aryl, C₇-C₂₄ alkaryl, C₇-C₂₄aralkyl, halo substituted C₁₋₆ alkyl up to per halo alkyl, halosubstituted C₆-C₁₂ aryl up to per halo aryl, halo substituted C₃-C₁₂cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to perhalo cycloalkyl, halo substituted C₃-C₁₂ hetaryl up to per haloheteraryl, halo substituted C₇-C₂₄ aralkyl up to per halo aralkyl, halosubstituted C₇-C₂₄ alkaryl up to per halo alkaryl, and —C(O)R_(g), or c)one of R_(a) or R_(b) is —C(O)—, a C₁-C₅ divalent alkylene group or asubstituted C₁-C₅ divalent alkylene group bound to the moiety L to forma cyclic structure with at least 5 members, wherein the substituents ofthe substituted C₁-C₅ divalent alkylene group are selected from thegroup consisting of halogen, hydroxy, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkylhaving 0-3 heteroatoms selected from O, S and N, C₃₋₁₂ hetaryl having1-3 heteroatoms selected from N, S and O, C₁₋₁₀ alkoxy, C₆₋₁₂ aryl,C₇-C₂₄ alkaryl, C₇-C₂₄ aralkyl, C₁₋₆ halo substituted alkyl up to perhalo alkyl, C₆-C₁₂ halo substituted aryl up to per halo aryl, C₃-C₁₂halo substituted cycloalkyl having 0-3 heteroatoms selected from N, Sand O, up to per halo cycloalkyl, halo substituted C₃-C₁₂ hetaryl up toper halo heteraryl, halo substituted C₇-C₂₄ aralkyl up to per haloaralkyl, halo substituted C₇-C₂₄ alkaryl up to per halo alkaryl, and—C(O)R_(g), where R_(g) is C₁₋₁₀ alkyl; —CN, —CO₂R_(d), —OR_(d),—SR_(d), —NO₂, —C(O)R_(e), —NR_(d)R_(e), —NR_(d)C(O)OR_(e) and—NR_(d)C(O)R_(e), and R_(d) and R_(e) are independently selected fromthe group consisting of hydrogen, C₁₋₁₀, alkyl, C₁₋₁₀ alkoxy, C₃₋₁₀cycloalkyl having 0-3 heteroatoms selected from O, N and S, C₆₋₁₂ aryl,C₃-C₁₂ hetaryl with 1-3 heteroatoms selected from O, N and S and C₇-C₂₄aralkyl, C₇-C₂₄ alkaryl, up to per halo substituted C₁-C₁₀ alkyl, up toper halo substituted C₃-C₁₀ cycloalkyl having 0-3 heteroatoms selectedfrom O, N and S, up to per halo substituted C₆-C₁₄ aryl, up to per halosubstituted C₃-C₁₂ hetaryl having 1-3 heteroatoms selected from O, N,and S, halo substituted C₇-C₂₄ alkaryl up to per halo alkaryl, and up toper halo substituted C₇-C₂₄ aralkyl, W is independently selected fromthe group consisting of —CN, —CO₂R⁷, —C(O)NR⁷R⁷, —C(O)—R⁷, —NO₂, —OR⁷,—SR⁷, —NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy,C₂-C₁₀ alkenyl, C₁-C₁₀ alkenoyl, C₃-C₁₀ cycloalkyl having 0-3heteroatoms selected from O, S and N, C₆-C₁₄ aryl, C₇-C₂₄ alkaryl,C₇-C₂₄ aralkyl, C₃-C₁₂ heteroaryl having 1-3 heteroatoms selected fromO, N and S, C₄-C₂₃ alkheteroaryl having 1-3 heteroatoms selected from O,N and S, substituted C₁-C₁₀ alkyl, substituted C₁-C₁₀ alkoxy,substituted C₂-C₁₀ alkenyl, substituted C₁-C₁₀ alkenoyl, substitutedC₃-C₁₀ cycloalkyl having 0-3 heteroatoms selected from O, N and S,substituted C₆-C₁₂ aryl, substituted C₃-C₁₂ hetaryl having 1-3heteroatoms selected from O, N and S, substituted C₇-C₂₄ aralkyl,substituted C₇-C₂₄ alkaryl, substituted C₄-C₂₃ alkheteroaryl having 1-3heteroatoms selected from O, N and S, and —Q—Ar; R⁷ is independentlyselected from H, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₂-C₁₀ alkenyl, C₁-C₁₀alkenoyl, C₃-C₁₀ cycloalkyl having 0-3 heteroatoms selected from O, Sand N, C₆-C₁₄ aryl, C₃-C₁₃ hetaryl having 1-3 heteroatoms selected fromO, N and S, C₇-C₁₄ alkaryl, C₇-C₂₄ aralkyl, C₄-C₂₃ alkheteroaryl having1-3 heteroatoms selected from O, N and S, up to per-halosubstitutedC₁-C₁₀ alkyl, up to per-halosubstituted C₃-C₁₀ cycloalkyl having 0-3heteroatoms selected from O, N and S, up to per-halosubstituted C₆-C₁₄aryl, up to per-halosubstituted C₃-C₁₃ hetaryl having 1-3 heteroatomsselected from O, N and S, up to per-halosubstituted C₇-C₂₄ aralkyl, upto per-halosubstituted C₇-C₂₄ alkaryl, and up to per-halosubstitutedC₄-C₂₃ alkheteroaryl; and each Z is independently selected from thegroup consisting of —CN, —CO₂R⁷, —C(O)R⁷, —C(O)NR⁷R⁷, —NO₂, —OR⁷,—SR⁷—NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₂-C₁₀alkenyl, C₁-C₁₀ alkenoyl, C₃-C₁₀ cycloalkyl having 0-3 heteroatomsselected from O, N and S, C₆-C₁₄ aryl, C₃-C₁₃ hetaryl having 1-3heteroatoms selected from O, N and S, C₇-C₂₄ alkaryl, C₇-C₂₄ aralkyl,C₄-C₂₃ alkheteroaryl having 1-3 heteroatoms selected from O, N and S,substituted C₁-C₁₀ alkyl, substituted C₁-C₁₀ alkoxy, substituted C₂-C₁₀alkenyl, substituted C₁-C₁₀ alkenoyl, substituted C₃-C₁₀ cycloalkylhaving 0-3 heteroatoms selected from O, N and S, substituted C₆-C₁₂aryl, substituted C₇-C₂₄ alkaryl, substituted C₇-C₂₄ aralkyl andsubstituted C₄-C₂₃ alkheteroaryl having 1-3 heteroatoms selected from O,N and S; wherein if Z is a substituted group, the one or moresubstituents are selected from the group consisting of —CN, —CO₂R⁷,—COR⁷, —C(O)NR⁷R⁷, —OR⁷, —SR⁷, —NO₂, —NR⁷R⁷, —NR⁷C(O)R⁷, and—NR⁷C(O)OR⁷.
 3. A compound as in claim 1 wherein M is one or morebridging groups selected from the group consisting of —O—, —S—, —N(R⁷)—,—(CH₂)_(m)—, —C(O)—, —CH(OH)—, —(CH₂)_(m)O—, —(CH₂)_(m)S—,—(CH₂)_(m)N(R⁷)—, —O(CH₂)_(m) 13 CHX^(a)—, —CX^(a) ₂—, —S—(CH₂)_(m)— and—N(R⁷)(CH₂)_(m)—, where m=1-3, X^(a) is halogen and R⁷ is as defined inclaim
 1. 4. A compound as in claim 1 wherein the cyclic structures of Band L bound directly to D are not substituted in the ortho position by—OH.
 5. A compound as in claim 1 wherein the cyclic structures of B andL bound directly to D are not substituted in the ortho position by amoiety having an ionizable hydrogen and a pKa of 10 or less.
 6. Acompound of claim 1 wherein B of Formula I is a substituted orunsubstituted six member aryl moiety or six member hetaryl moiety, saidhetaryl moiety having 1 to 4 members selected from the group of hetarylatoms consisting of nitrogen, oxygen and sulfur with the balance of thehetaryl moiety being carbon.
 7. A compound of claim 1 wherein B ofFormula I is an unsubstituted phenyl group, an unsubstituted pyridylgroup, an unsubstituted pyrimidinyl, a phenyl group substituted by asubstituent selected from the group consisting of halogen and Wn whereinW and n are as defined in claim 1, a pyrimidinyl group substituted by asubstituent selected from the group constituting of halogen and Wn,whereas W and n are as defined in claim 1, or a substituted pyridylgroup substituted by a substituent selected from the group consisting ofhalogen and Wn wherein W and n are as defined in claim
 1. 8. A compoundof claim 6 wherein B of Formula I is a substituted phenyl group, asubstituted pyrimidinyl group, or substituted pyrridyl group substituted1 to 3 times by 1 or more substituents selected from the groupconsisting of —CN, halogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, —OH, up to perhalo substituted C₁-C₁₀ alkyl, up to per halo substituted C₁-C₁₀ alkoxyor phenyl substituted by halogen up to per halo.
 9. A compound of claim1, wherein L, the six member cyclic structure bound directly to D, is asubstituted or unsubstituted 6 member aryl moiety or a substituted orunsubstituted 6 member hetaryl moiety, wherein said hetaryl moiety has 1to 4 members selected from the group of heteroatoms consisting ofnitrogen, oxygen and sulfur with the balance of said hetaryl moietybeing carbon, wherein the one or more substituents are selected from thegroup consisting of halogen and Wn wherein W and n are as defined inclaim
 1. 10. A compound of claim 8, wherein L, the 6 member cyclicstructure bound directly to D, is a substituted phenyl, unsubstitutedphenyl, substituted pyrimidinyl, unsubstituted pyrimidinyl, substitutedpyridyl or unsubstituted pyridyl group.
 11. A compound of claim 1,wherein said substituted cyclic moiety L¹ comprises a 5 to 6 memberedaryl moiety or hetaryl moiety, wherein said heteraryl moiety comprises 1to 4 members selected from the group of heteroatoms consisting ofnitrogen, oxygen and sulfur.
 12. A compound of claim 1, wherein saidsubstituted cyclic moiety L¹ is phenyl, pyridinyl or pyrimidinyl.
 13. Acompound of claim 3, wherein said substituted cyclic moiety L¹ isphenyl, pyridinyl or pyrimidinyl.
 14. A compound of claim 6, whereinsaid substituted cyclic moiety L¹ is phenyl, pyridinyl or pyrimidinyl.15. A compound of claim 8, wherein said substituted cyclic moiety L¹ isphenyl, pyridinyl or pyrimidinyl.
 16. A compound of claim 9, whereinsaid substituted cyclic moiety L¹ is phenyl, pyridinyl or pyrimidinyl.17. A compound of claim 10, wherein said substituted cyclic moiety L¹ isphenyl, pyridinyl or pyrimidinyl.
 18. A compound of claim 14, wherein Mis one or more bridging groups selected from the group consisting of—O—, —S—, —N(R⁷)—, —(CH₂)_(m)—, —C(O)—, —CH(OH)—, —(CH₂)_(m)O—,—(CH₂)_(m)S—, —(CH₂)_(m)N(R⁷)—, —O(CH₂)_(m)—CHX^(a)—, —CX^(a) ₂—,—S—(CH₂)_(m)— and —N(R⁷)(CH₂)_(m)—, where m=1-3, X^(a) is halogen and R⁷is hydrogen or a carbon based moiety of up to 24 carbon atoms,optionally containing heteroatoms selected from N, S and O andoptionally substituted by halogen up to per halo.
 19. A compound ofclaim 15, wherein M is one or more bridging groups selected from thegroup consisting of —O—, —S—, —N(R⁷)—, —(CH₂)_(m)—, —C(O)—, —CH(OH)—,—(CH₂)_(m)O—, —(CH₂)_(m)S—, —(CH₂)_(m)N(R⁷)—, —O(CH₂)_(m)—CHX^(a)—,—CX^(a) ₂—, —S—(CH₂)_(m)— and —N(R⁷)(CH₂)_(m)—, where m=1-3, X^(a) ishalogen and R⁷ is hydrogen or a carbon based moiety of up to 24 carbonatoms, optionally containing heteroatoms selected from N, S and O andoptionally substituted by halogen up to per halo.
 20. A compound ofclaim 16, wherein M is one or more bridging groups selected from thegroup consisting of —O—, —S—, —N(R⁷)—, —(CH₂)_(m)—, —C(O)—, —CH(OH)—,—(CH₂)_(m)O—, —(CH₂)_(m)S—, —(CH₂)_(m)N(R⁷)—, —O(CH₂)_(m)—CHX^(a)—,—CX^(a) ₂—, —S—(CH₂)_(m)— and —N(R⁷)(CH₂)_(m)—, where m=1-3, X^(a) ishalogen and R⁷ is hydrogen or a carbon based moiety of up to 24 carbonatoms, optionally containing heteroatoms selected from N, S and O andoptionally substituted by halogen up to per halo.
 21. A compound ofclaim 17, wherein M is one or more bridging groups selected from thegroup consisting of —O—, —S—, —N(R⁷)—, —(CH₂)_(m)—, —C(O)—, —CH(OH)—,—(CH₂)_(m)O—, —(CH₂)_(m)S—, —(CH₂)_(m)N(R⁷)—, —O(CH₂)_(m)—CHX^(a)—,—CX^(a) ₂—, —S—(CH₂)_(m)— and —N(R⁷)(CH₂)_(m)—, where m=1-3, X^(a) ishalogen and R⁷ is hydrogen or a carbon based moiety of Up to 24 carbonatoms, optionally containing heteroatoms selected from N, S and O andoptionally substituted by halogen up to per halo.
 22. A compound ofclaim 1 wherein L¹ is additionally substituted 1 to 3 times by one ormore substituents selected from the group consisting of C₁-C₁₀ alkyl, upto per halo substituted C₁-C₁₀ alkyl, —CN, —OH, halogen, C₁-C₁₀ alkoxyand up to per halo substituted C₁-C₁₀ alkoxy.
 23. A compound of claim 13wherein L¹ is additionally substituted 1 to 3 times by one or moresubstituents selected from the group consisting of C₁-C₁₀ alkyl, up toper halo substituted C₁-C₁₀ alkyl, —CN, —OH, halogen, C₁-C₁₀ alkoxy andup to per halo substituted C₁-C₁₀ alkoxy.
 24. A compound of claim 18wherein L¹ is additionally substituted 1 to 3 times by one or moresubstituents selected from the group consisting of C₁-C₁₀ alkyl, up toper halo substituted C₁-C₁₀ alkyl, —CN, —OH, halogen, C₁-C₁₀ alkoxy andup to per halo substituted C₁-C₁₀ alkoxy.
 25. A compound of claim 19wherein L¹ is additionally substituted 1 to 3 times by one or moresubstituents selected from the group consisting of C₁-C₁₀ alkyl, up toper halo substituted C₁-C₁₀ alkyl, —CN, —OH, halogen, C₁-C₁₀ alkoxy andup to per halo substituted C₁-C₁₀ alkoxy.
 26. A compound of claim 20wherein L¹ is additionally substituted 1 to 3 times by one or moresubstituents selected from the group consisting of C₁-C₁₀ alkyl, up toper halo substituted C₁-C₁₀ alkyl, —CN, —OH, halogen, C₁-C₁₀ alkoxy andup to per halo substituted C₁-C₁₀ alkoxy.
 27. A compound of claim 21wherein L¹ is additionally substituted 1 to 3 times by one or moresubstituents selected from the group consisting of C₁-C₁₀ alkyl, up toper halo substituted C₁C₁₀ alkyl, —CN, —OH, halogen, C₁-C₁₀ alkoxy andup to per halo substituted C₁-C₁₀ alkoxy.
 28. A compound of claim 1wherein L¹ is substituted by —C(O)R_(x).
 29. A compound of claim 1wherein L¹ is substituted by —SO₂R_(x).
 30. A compound of claim 1wherein L¹ is substituted only by —C(O)R_(x).
 31. A compound of claim 1wherein L¹ is substituted only by —SO₂R_(x).
 32. A compound of claim 1wherein L¹ is substituted by —C(O)R_(x) or —SO₂R_(x), wherein R_(x) isNR_(a)R_(b).
 33. A compound of claim 13 wherein L¹ is substituted by—C(O)R_(x) or —SO₂R_(x), wherein R_(x) is NR_(a)R_(b), and R_(a) andR_(b) are a) independently hydrogen, a carbon based moiety of up to 30carbon atoms optionally containing heteroatoms selected from N, S and Oand optionally substituted by halogen, hydroxy and carbon basedsubstituents of up to 24 carbon atoms, which optionally containheteroatoms selected from N, S and O and are optionally substituted byhalogen, or —OSi(R_(f))₃ where R_(f) is hydrogen or a carbon basedmoiety of up to 24 carbon atoms optionally containing heteroatomsselected from N, S and O and optionally substituted by halogen, hydroxyand carbon based substituents of up to 24 carbon atoms, which optionallycontain heteroatoms selected from N, S and O and are optionallysubstituted by halogen; or b) R_(a) and R_(b) together form a 5-7 memberheterocyclic structure of 1-3 heteroatoms selected from N, S and O, or asubstituted 5-7 member heterocyclic structure of 1-3 heteroatomsselected from N, S and O substituted by halogen, hydroxy or carbon basedsubstituents of up to 24 carbon atoms, which optionally containheteroatoms selected from N, S and O and are optionally substituted byhalogen; or c) one of R_(a) or R_(b) is —C(O)—, a C₁-C₅ divalentalkylene group or a substituted C₁-C₅ divalent alkylene group bound tothe moiety L to form a cyclic structure with at least 5 members, whereinthe substituents of the substituted C₁-C₅ divalent alkylene group areselected from the group consisting of halogen, hydroxy, and carbon basedsubstituents of up to 24 carbon atoms, which optionally containheteroatoms selected from N, S and O and are optionally substituted byhalogen.
 34. A compound of claim 18 wherein L¹ is substituted by—C(O)R_(x) or —SO₂R_(x), wherein R_(x) is NR_(a)R_(b) and R_(a) andR_(b) are independently hydrogen or a carbon based moiety of up to 30carbon atoms optionally containing heteroatoms selected from N, S and Oand optionally substituted by halogen, hydroxy and carbon basedsubstituents of up to 24 carbon atoms, which optionally containheteroatoms selected from N, S and O and are optionally substituted byhalogen.
 35. A compound of claim 19 wherein L¹ is substituted by—C(O)R_(x), wherein R_(x) is NR_(a)R_(b) and R_(a) and R_(b) areindependently hydrogen or a carbon based moiety of up to 30 carbon atomsoptionally containing heteroatoms selected from N, S and O andoptionally substituted by halogen, hydroxy and carbon based substituentsof up to 24 carbon atoms, which optionally contain heteroatoms selectedfrom N, S and O and are optionally substituted by halogen.
 36. Acompound of claim 20 wherein L¹ is substituted by —C(O)R_(x) or—SO₂R_(x), wherein R_(x) is NR_(a)R_(b) and R_(a) and R_(b) areindependently hydrogen or a carbon based moiety of up to 30 carbon atomsoptionally containing heteroatoms selected from N, S and O andoptionally substituted by halogen, hydroxy and carbon based substituentsof up to 24 carbon atoms, which optionally contain heteroatoms selectedfrom N, S and O and are optionally substituted by halogen.
 37. Acompound of claim 21 wherein L¹ is substituted by —C(O)R_(x) or—SO₂R_(x), wherein R_(x) is NR_(a)R_(b) and R_(a) and R_(b) areindependently hydrogen or a carbon based moiety of up to 30 carbon atomsoptionally containing heteroatoms selected from N, S and O andoptionally substituted by halogen, hydroxy and carbon based substituentsof up to 24 carbon atoms, which optionally contain heteroatoms selectedfrom N, S and O and are optionally substituted by halogen.
 38. Acompound of Formula I: A—D—B  (I) or a pharmaceutically acceptable saltthereof, wherein D is —NH—C(O)—NH—, A is a substituted moiety of up to40 carbon atoms of the formula: —L—(M—L¹)_(q), where L is a 6 memberedaryl moiety or a 6 membered hetaryl moiety bound directly to D, L¹comprises a substituted cyclic moiety having at least 5 members, M is abridging group having at least one atom, q is an integer of from 1-3;and each cyclic structure of L and L¹ contains 0-4 members of the groupconsisting of nitrogen, oxygen and sulfur, and B is a substituted orunsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30carbon atoms with at least one 6-member cyclic structure bound directlyto D containing 0-4 members of the group consisting of nitrogen, oxygenand sulfur, wherein L¹ is substituted by at least one substituentselected from the group consisting of —SO₂R_(x), —C(O)R_(x) and—C(NR_(y))R_(z), R_(y) is hydrogen or a carbon based moiety of up to 24carbon atoms optionally containing heteroatoms selected from N, S and Oand optionally halosubstituted, up to per halo, R_(z) is hydrogen or acarbon based moiety of up to 30 carbon atoms optionally containingheteroatoms selected from N, S and O and optionally substituted byhalogen, hydroxy and carbon based substituents of up to 24 carbon atoms,which optionally contain heteroatoms selected from N, S and O and areoptionally substituted by halogen; R_(x) is R_(z) or NR_(a)R_(b) whereR_(a) and R_(b) are a) independently hydrogen, a carbon based moiety ofup to 30 carbon atoms optionally containing heteroatoms selected from N,S and O and optionally substituted by halogen, hydroxy and carbon basedsubstituents of up to 24 carbon atoms, which optionally containheteroatoms selected from N, S and O and are optionally substituted byhalogen, or —OSi(R_(f))₃ where R_(f) is hydrogen or a carbon basedmoiety of up to 24 carbon atoms optionally containing heteroatomsselected from N, S and O and optionally substituted by halogen, hydroxyand carbon based substituents of up to 24 carbon atoms, which optionallycontain heteroatoms selected from N, S and O and are optionallysubstituted by halogen; or b) R_(a) and R_(b) together form a 5-7 memberheterocyclic structure of 1-3 heteroatoms selected from N, S and O, or asubstituted 5-7 member heterocyclic structure of 1-3 heteroatomsselected from N, S and O substituted by halogen, hydroxy or carbon basedsubstituents of up to 24 carbon atoms, which optionally containheteroatoms selected from N, S and O and are optionally substituted byhalogen; or c) one of R_(a) or R_(b) is —C(O)—, a C₁-C₅ divalentalkylene group or a substituted C₁-C₅ divalent alkylene group bound tothe moiety L to form a cyclic structure with at least 5 members, whereinthe substituents of the substituted C₁-C₅ divalent alkylene group areselected from the group consisting of halogen, hydroxy, and carbon basedsubstituents of up to 24 carbon atoms, which optionally containheteroatoms selected from N, S and O and are optionally substituted byhalogen; where B is substituted, L is substituted or L¹ is additionallysubstituted, the substituents are selected from the group consisting ofhalogen, up to per-halo, and Wn, where n is 0-3; wherein each W isindependently selected from the group consisting of —CN, —CO₂R⁷,—C(O)NR⁷R⁷, —C(O)—R⁷, —NO₂, —OR⁷, —SR⁷, —NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷,—Q—Ar, and carbon based moieties of up to 24 carbon atoms, optionallycontaining heteroatoms selected from N, S and O and optionallysubstituted by one or more substituents independently selected from thegroup consisting of —CN, —CO₂R⁷, —C(O)R⁷, —C(O)NR⁷R⁷, —OR⁷, —SR⁷,—NR⁷R⁷, —NO₂, —NR⁷C(O)R⁷, —NR⁷C(O)OR⁷ and halogen up to per-halo; witheach R⁷ independently selected from H or a carbon based moiety of up to24 carbon atoms, optionally containing heteroatoms selected from N, Sand O and optionally substituted by halogen, wherein Q is —O—, —S—,—N(R⁷)—, —(CH₂)_(m)—, —C(O)—, —CH(OH)—, —(CH₂)_(m)O—, —(CH₂)_(m)S—,—(CH₂)_(m)N(R⁷)—, —O(CH₂)_(m)—CHX^(a)—, —CX^(a) ₂—, —S—(CH₂)_(m)— and—N(R⁷)(CH₂)_(m)—, where m=1-3, and X^(a) is halogen; Ar is a 5- or6-member aromatic structure containing 0-2 members selected from thegroup consisting of nitrogen, oxygen and sulfur, which is optionallysubstituted by halogen, up to per-halo, and optionally substituted byZ_(n1), wherein n1 is 0 to 3 and each Z is independently selected fromthe group consisting of —CN, —CO₂R⁷, —C(O)R⁷, —C(O)NR⁷R⁷, —NO₂, —OR⁷,—SR⁷—NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, and a carbon based moiety of up to24 carbon atoms, optionally containing heteroatoms selected from N, Sand O and optionally substituted by one or more substituents areselected from the group consisting of —CN, —CO₂R⁷, —COR⁷, —C(O)NR⁷R⁷,—OR⁷, —SR⁷, —NO₂, —NR⁷R⁷, —NR⁷C(O)R⁷, and —NR⁷C(O)OR⁷, with R⁷ asdefined above; and wherein M is one or more bridging groups selectedfrom the group consisting of —O—, —S—, —N(R⁷)—, —(CH₂)_(m)—, —C(O)—,—CH(OH)—, —(CH₂)_(m)O—, —(CH₂)_(m)S—, —(CH₂)_(m)N(R⁷)—,—O(CH₂)_(m)—CHX^(a)—, —CH^(a) ₂—, —S—(CH₂)_(m)— and —N(R⁷)(CH₂)_(m)—,where m=1-3, X^(a) is halogen.
 39. A compound of Formula I: A—D—B  (I)or a pharmaceutically acceptable salt thereof, wherein D is—NH—C(O)—NH—, A is a substituted moiety of up to 40 carbon atoms of theformula: —L—(M—L¹)_(q), where L is a substituted or unsubstituted phenylor peritoneal moiety bound directly to D, L¹ comprises a substitutedphenyl, peritoneal or pyrimidinyl moiety, M is a bridging group havingat least one atom, q is an integer of from 1-3; and B is a substitutedor unsubstituted phenyl or pyridine group bound directly to D, whereinL¹ is substituted by at least one substituent selected from the groupconsisting of —SO₂R_(x), —C(O)R_(x) and —C(NR_(y))R_(z), R_(y) ishydrogen or a carbon based moiety of up to 24 carbon atoms optionallycontaining heteroatoms selected from N, S and O and optionallyhalosubstituted, up to per halo, and; R_(z) is hydrogen or a carbonbased moiety of up to 30 carbon atoms optionally containing heteroatomsselected from N, S and O and optionally substituted by halogen, hydroxyand carbon based substituents of up to 24 carbon atoms, which optionallycontain heteroatoms selected from N, S and O and are optionallysubstituted by halogen; p2 R_(x) is R_(z) or NR_(a)R_(b) where R_(a) andR_(b) are a) independently hydrogen, a carbon based moiety of up to 30carbon atoms optionally containing heteroatoms selected from N, S and Oand optionally substituted by halogen, hydroxy and carbon basedsubstituents of up to 24 carbon atoms, which optionally containheteroatoms selected from N, S and O and are optionally substituted byhalogen, or —OSi(R_(f))₃ where R_(f) is hydrogen or a carbon basedmoiety of up to 24 carbon atoms optionally containing heteroatomsselected from N, S and O and optionally substituted by halogen, hydroxyand carbon based substituents of up to 24 carbon atoms, which optionallycontain heteroatoms selected from N, S and O and are optionallysubstituted by halogen; or b) R_(a) and R_(b) together form a 5-7 memberheterocyclic structure of 1-3 heteroatoms selected from N, S and O, or asubstituted 5-7 member heterocyclic structure of 1-3 heteroatomsselected from N, S and O substituted by halogen, hydroxy or carbon basedsubstituents of up to 24 carbon atoms, which optionally containheteroatoms selected from N, S and O and are optionally substituted byhalogen; or c) one of R_(a) or R_(b) is —C(O)—, a C₁-C₅ divalentalkylene group or a substituted C₁-C₅ divalent alkylene group bound tothe moiety L to form a cyclic structure with at least 5 members, whereinthe substituents of the substituted C₁-C₅ divalent alkylene group areselected from the group consisting of halogen, hydroxy, and carbon basedsubstituents of up to 24 carbon atoms, which optionally containheteroatoms selected from N, S and O and are optionally substituted byhalogen; where B is substituted, L is substituted or L¹ is additionallysubstituted, the substituents are selected from the group consisting ofhalogen, up to per-halo, and Wn, where n is 0-3; wherein each W isindependently selected from the group consisting of —CN, —CO₂R⁷,—C(O)NR⁷R⁷, —C(O)—R⁷, —NO₂, —OR⁷, —SR⁷, —NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷,—Q—Ar, and carbon based moieties of up to 24 carbon atoms, optionallycontaining heteroatoms selected from N, S and O and optionallysubstituted by one or more substituents independently selected from thegroup consisting of —CN, —CO₂R⁷, —C(O)R⁷, —C(O)NR⁷R⁷, —OR⁷, —SR⁷,—NR⁷R⁷, —NO₂, —NR⁷C(O)R⁷, —NR⁷C(O)OR⁷ and halogen up to per-halo; witheach R⁷ independently selected from H or a carbon based moiety of up to24 carbon atoms, optionally containing heteroatoms selected from N, Sand O and optionally substituted by halogen, wherein Q is —O—, —S—,—N(R⁷)—, —(CH₂)_(m)—, —C(O)—, —CH(OH)—, —(CH₂)_(m)O—, —(CH₂)_(m)S—,—(CH₂)_(m)N(R⁷)—, —O(CH₂)_(m)—CHX^(a)—, —CX^(a) ₂ 13 , —S—(CH₂)_(m)— and—N(R⁷)(CH₂)_(m)—, where m=1-3, and X^(a) is halogen; Ar is a 5- or6-member aromatic structure containing 0-2 members selected from thegroup consisting of nitrogen, oxygen and sulfur, which is optionallysubstituted by halogen, up to per-halo, and optionally substituted byZ_(n1), wherein n1 is 0 to 3 and each Z is independently selected fromthe group consisting of —CN, —CO₂R⁷, —C(O)R⁷, —C(O)NR⁷R⁷, —NO₂, —OR⁷,—SR⁷—NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, and a carbon based moiety of up to24 carbon atoms, optionally containing heteroatoms selected from N, Sand O and optionally substituted by one or more substituents selectedfrom the group consisting of —CN, —CO₂R⁷, —COR⁷, —C(O)NR⁷R⁷, —OR⁷, —SR⁷,—NO₂, —NR⁷R⁷, —NR⁷C(O)R⁷, and —NR⁷C(O)OR⁷; and wherein M is one or morebridging groups selected from the group consisting of —O—, —S—, —N(R⁷)—,—(CH₂)_(m)—, —C(O)—, —CH(OH)—, —(CH₂)_(m)O—, —(CH₂)_(m)S—,—(CH₂)_(m)N(R⁷)—, —O(CH₂)_(m)—CHX^(a), 13 CX^(a) ₂—, —S—(CH₂)_(m)— and—N(R⁷)(CH₂)_(m)—, where m=1-3, X^(a) is halogen.
 40. A compound as inclaim 38 wherein the cyclic structures of B and L bound directly to Dare not substituted in the ortho position by —OH.
 41. A compound as inclaim 38 wherein the cyclic structures of B and L bound directly to Dare not substituted in the ortho position by a moiety having anionizable hydrogen and a pKa of 10 or less.
 42. A compound as in claim39 wherein the cyclic structures of B and L bound directly to D are notsubstituted in the ortho position by —OH.
 43. A compound as in claim 39wherein the cyclic structures of B and L bound directly to D are notsubstituted in the ortho position by a moiety having an ionizablehydrogen and a pKa of 10 or less.
 44. A compound as in claim 38 whereinsubstituents for B and L and additional substituents for L¹, areselected from the group consisting of C₁-C₁₀alkyl up to per halosubstituted C₁-C₁₀ alkyl, CN, OH, halogen, C₁-C₁₀ alkoxy and up to perhalo substituted C₁-C₁₀ alkoxy.
 45. A compound as in claim 39 whereinsubstituents for B and L and additional substituents for L¹, areselected from the group consisting of C₁-C₁₀ alkyl up to per halosubstituted C₁-C₁₀ alkyl, CN, OH, halogen, C₁-C₁₀ alkoxy and up to perhalo substituted C₁-C₁₀ alkoxy.
 46. A compound of claim 38 wherein L¹ issubstituted by C(O)R_(x) or SO₂R_(x).
 47. A compound of claim 39 whereinL¹ is substituted by C(O)R_(x) or SO₂R_(x).
 48. A compound of claim 46wherein R_(x) is NR_(a)R_(b) and R_(a) and R_(b) are independentlyhydrogen and a carbon based moiety of up to 30 carbon atoms optionallycontaining heteroatoms selected from N, S and O and optionallysubstituted by halogen, hydroxy and carbon based substituents of up to24 carbon atoms, which optionally contain heteroatoms selected from N, Sand O and are optionally substituted by halogen..
 49. A compound ofclaim 47 wherein R_(x) is NR_(a)R_(b) and R_(a) and R_(b) areindependently hydrogen and a carbon based moiety of up to 30 carbonatoms optionally containing heteroatoms selected from N, S and O andoptionally substituted by halogen, hydroxy and carbon based substituentsof up to 24 carbon atoms, which optionally contain heteroatoms selectedfrom N, S and O and are optionally substituted by halogen.
 50. Acompound of claim 1 which is a pharmaceutically acceptable salt of acompound of formula I selected from the group consisting of a) basicsalts of organic acids and inorganic acids selected from the groupconsisting of hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methanesulphonic acid, trifluorosulphonic acid,benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt),1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid,trifluoroacetic acid, malic acid, tartaric acid, citric acid, lacticacid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoicacid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acidsalts of organic and inorganic bases containing cations selected fromthe group consisting of alkaline cations, alkaline earth cations, theammonium cation, aliphatic substituted ammonium cations and aromaticsubstituted ammonium cations.
 51. A compound of claim 2 which is apharmaceutically acceptable salt of a compound of formula I selectedfrom the group consisting of a) basic salts of organic acids andinorganic acids selected from the group consisting of hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonicacid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonicacid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonicacid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid,citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid,maleic acid, benzoic acid, salicylic acid, phenylacetic acid, andmandelic acid; and b) acid salts of organic and inorganic basescontaining cations selected from the group consisting of alkalinecations, alkaline earth cations, the ammonium cation, aliphaticsubstituted ammonium cations and aromatic substituted ammonium cations.52. A compound of claim 33 which is a pharmaceutically acceptable saltof a compound of formula I selected from the group consisting of a)basic salts of organic acids and inorganic acids selected from the groupconsisting of hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methanesulphonic acid, trifluorosulphonic acid,benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt),1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid,trifluoroacetic acid, malic acid, tartaric acid, citric acid, lacticacid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoicacid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acidsalts of organic and inorganic bases containing cations selected fromthe group consisting of alkaline cations, alkaline earth cations, theammonium cation, aliphatic substituted ammonium cations and aromaticsubstituted ammonium cations.
 53. A compound of claim 38 which is apharmaceutically acceptable salt of a compound of formula I selectedfrom the group consisting of a) basic salts of organic acids andinorganic acids selected from the group consisting of hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonicacid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonicacid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonicacid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid,citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid,maleic acid, benzoic acid, salicylic acid, phenylacetic acid, andmandelic acid; and b) acid salts of organic and inorganic basescontaining cations selected from the group consisting of alkalinecations, alkaline earth cations, the ammonium cation, aliphaticsubstituted ammonium cations and aromatic substituted ammonium cations.54. A compound of claim 39 which is a pharmaceutically acceptable saltof a compound of formula I selected from the group consisting of a)basic salts of organic acids and inorganic acids selected from the groupconsisting of hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methanesulphonic acid, trifluorosulphonic acid,benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt),1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid,trifluoroacetic acid, malic acid, tartaric acid, citric acid, lacticacid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoicacid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acidsalts of organic and inorganic bases containing cations selected fromthe group consisting of alkaline cations, alkaline earth cations, theammonium cation, aliphatic substituted ammonium cations and aromaticsubstituted ammonium cations.
 55. A pharmaceutical compositioncomprising a compound of claim 1 or a pharmaceutically acceptable saltof a compound of formula I, and a physiologically acceptable carrier.56. A pharmaceutical composition comprising a compound of claim 2consistent with formula I or a pharmaceutically acceptable salt thereof,and a physiologically acceptable carrier.
 57. A pharmaceuticalcomposition comprising a compound of claim 33 consistent with formula Ior a pharmaceutically acceptable salt thereof, and a physiologicallyacceptable carrier.
 58. A pharmaceutical composition comprising acompound of claim 38 consistent with formula I or a pharmaceuticallyacceptable salt thereof, and a physiologically acceptable carrier.
 59. Apharmaceutical composition comprising a compound of claim 39 consistentwith formula I or a pharmaceutically acceptable salt thereof and aphysiologically acceptable carrier.
 60. A compound selected from thegroup consisting of 3-tert butyl phenyl ureas of Table 1 above; 5-tertbutyl-2-methoxyphenyl ureas of Table 2 above; 5-(trifluoromethyl)-2phenyl ureas of Table 3 above; 3-(trifluoromethyl)-4 chlorophenyl ureasof Table 4 above; 3-(trifluoromethyl)-4-bromophenyl ureas of Table 5above; 5-(trifluoromethyl)-4-chloro-2 methoxyphenyl ureas of Table 6above; and ureas 101-103 in Table 7 above.
 61. A compound selected fromthe group consisting of the 3-tert butyl phenyl ureas:N-(3-tert-butylphenyl)-N′-(4-(3-(N-methylcarbamoyl)phenoxy)phenyl ureaand N-(3-tert-butylphenyl)-N′-(4-(4-acetylphenoxy)phenyl urea; the5-tert-butyl-2-methoxyphenyl ureas:N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl)urea,N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(1-oxoisoindolin-5-yloxy)phenyl)urea,N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(4-methoxy-3-(N-methylcarbamoyl)phenoxy)phenyl)urea andN-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(3-(N-methylcarbamoyl)phenoxy)phenyl)urea; the 2-methoxy-5-trifluoromethyl)phenyl ureas:N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(3-(2-carbamoyl-4-pyridyloxy)phenyl)urea,N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea,N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea,N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea,N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridylthio)phenyl)urea,N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea andN-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea; the 4-chloro-3-(trifluoromethyl)phenyl ureas:N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(3-(2-carbamoyl-4-pyridyloxy)phenyl)urea,N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea,N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea andN-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea. the 4-romo-3-(trifluoromethyl)phenyl ureas:N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea,N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea,N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridylthio)phenyl)urea,N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea andN-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea; and the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas:N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea,N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea,N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N′-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea andN-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N′-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea.
 62. A method for the treatment of a cancerous cell growth mediatedby raf kinase, comprising administering a compound of Formula I ofclaim
 1. 63. A method for the treatment of a cancerous cell growthmediated by raf kinase, comprising administering a compound of Formula Iof claim
 33. 64. A method for the treatment of a cancerous cell growthmediated by raf kinase, comprising administering a compound of Formula Iof claim
 38. 65. A method for the treatment of a cancerous cell growthmediated by raf kinase, comprising administering a compound of Formula Iof claim
 39. 66. A method for the treatment of a cancerous cell growthmediated by raf kinase, comprising administrating a compound selectedfrom the group consisting of 3-tert butyl phenyl ureas of Table 1 above;5-tert butyl-2-methoxyphenyl ureas of Table 2 above;5-(trifluoromethyl)-2 phenyl ureas of Table 3 above;3-(trifluoromethyl)-4 chlorophenyl ureas of Table 4 above;3-(trifluoromethyl)-4-bromophenyl ureas of Table 5 above;5-(trifluoromethyl)-4-chloro-2 methoxyphenyl ureas of Table 6 above; andureas 101-103 in Table 7 above.
 67. A method for the treatment of acancerous cell growth mediated by raf kinase, comprising administratinga compound selected from the group consisting of the 3-tert butyl phenylureas: N-(3-tert-butylphenyl)-N′-(4-(3-(N-methylcarbamoyl)phenoxy)phenylurea and N-(3-tert-butylphenyl)-N′-(4-(4-acetylphenoxy)phenyl urea; the5-tert-butyl-2-methoxyphenyl ureas:N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl)urea,N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(1-oxoisoindolin-5-yloxy)phenyl)urea,N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(4-methoxy-3-(N-methylcarbamoyl)phenoxy)phenyl)urea andN-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(3-(N-methylcarbamoyl)phenoxy)phenyl)urea; the 2-methoxy-5-trifluoromethyl)phenyl ureas:N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(3-(2-carbamoyl-4-pyridyloxy)phenyl)urea,N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea,N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea,N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea,N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridylthio)phenyl)urea,N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea andN-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea; the 4-chloro-3-(trifluoromethyl)phenyl ureas:N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(3-(2-carbamoyl-4-pyridyloxy)phenyl)urea,N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea,N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea andN-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea; the 4-romo-3-(trifluoromethyl)phenyl ureas:N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea,N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea,N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridylthio)phenyl)urea,N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea andN-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea; and the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas:N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N′-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea,N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea,N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N′-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea andN-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N′-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea.